Substituted 3-cyanoquinolines as MEK inhibitors

ABSTRACT

The invention concerns quinoline derivatives of Formula (I) wherein each of Z 1 , m, R 1 , n, R 3 , Z 2  and R 14  have any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an anti-invasive or anti-proliferative agent in the containment and/or treatment of solid tumour disease.

The invention concerns certain novel quinoline derivatives, orpharmaceutically-acceptable salts thereof, which possess anti-tumouractivity and are accordingly useful in methods of treatment of the humanor animal body. The invention also concerns processes for themanufacture of said quinoline derivatives, pharmaceutical compositionscontaining them and their use in therapeutic methods, for example in themanufacture of medicaments for use in the prevention or treatment ofsolid tumour disease in a warm-blooded animal such as man.

Many of the current treatment regimes for cell proliferation diseasessuch as psoriasis and cancer utilise compounds which inhibit DNAsynthesis. Such compounds are toxic to cells generally but their toxiceffect on rapidly dividing cells such as tumour cells can be beneficial.Alternative approaches to anti-tumour agents which act by mechanismsother than the inhibition of DNA synthesis have the potential to displayenhanced selectivity of action.

In recent years it has been discovered that a cell may become cancerousby virtue of the transformation of a portion of its DNA into an oncogenei.e. a gene which, on activation, leads to the formation of malignanttumour cells (Bradshaw, Mutagenesis, 1986, 1, 91). Oncogenes give riseto the production of peptides which are receptors for growth factors.Activation of the growth factor receptor complex subsequently leads toan increase in cell proliferation. Oncogenes often encode abnormalversions of signal pathway components, such as receptor tyrosinekinases, serine-threonine kinases, or downstream signaling moleculessuch as the ras genes. The ras genes code for closely related smallguanine nucleotide binding proteins which hydrolyse bound guanosinetriphosphate (GTP) to guanosine diphosphate (GDP). Ras proteins areactive in promoting cell growth and transformation when they are boundto GTP and inactive when they are bound to GDP. Transforming mutants ofp21ras are defective in their GTPase activity and hence remain in theactive GTP bound state. The ras oncogene is known to play an integralrole in certain cancers and has been found to contribute to theformation of over 20% of all cases of human cancer.

When activated by ligand such as a growth factor, cell surface receptorswhich are coupled to the mitogenic response can initiate a chain ofreactions which leads to the activation of guanine nucleotide exchangeactivity on ras proteins. When ras protein is in its active GTP-boundstate, a number of other proteins interact directly with ras at theplasma membrane resulting in signal transmission through severaldistinct pathways. The best characterised effector protein is theproduct of the raf proto-oncogene. The interaction of raf and ras is akey regulatory step in the control of cell proliferation. Ras-mediatedactivation of the raf serine-threonine kinase in turn activates thedual-specificity MEK (MEK1 and MEK2), which is the immediate upstreamactivator of mitogen activated protein kinase (MAPKs known asextracellular signal regulated protein kinases or ERK1 and ERK2). Todate, no substrates of MEK other than MAPK have been identified, thoughrecent reports indicate that MEK may also be activated by other upstreamsignal proteins such as MEKK1 and Cot/Tpl-2. Activated MAPK translocatesand accumulates in the nucleus, where it can phosphorylate and activatetranscription factors such as Elk-1 and Sap1a, leading to the enhancedexpression of genes such as c-fos.

The ras-dependent raf-MEK-MAPK cascade: is one of the key signallingpathways responsible for transmitting and amplifying mitogenic signalsfrom cell surface to the nucleus resulting in changes in gene expressionand cell fate. This ubiquitous pathway appears essential for normal-cellproliferation and constitutive activation of this pathway is sufficientto induce cellular transformation. Transforming mutants of p21ras areconstitutively active, resulting in raf, MEK and MAPK activity and celltransformation. Inhibition of MEK activity using either antisense raf, adominant negative MEK mutant or the selective inhibitor PD098059 hasbeen shown to block the growth and morphological transformation ofras-transformed fibroblasts.

The mechanism of activation of raf, MEK and MAPK is throughphosphorylation on specific serine, threonine or tyrosine residues.Activated raf and other kinases phosphorylate MEK1 on S218 and S222 andMEK2 on S222 and S226. This results in MEK activation and subsequentphosphorylation and activation of ERK1 on T190 and Y192 and ERK2 on T183and Y185 by the dual specificity MEKs. Whilst MEK can be activated by anumber of protein kinases, and active MAPKs phosphorylate and activate anumber of substrate proteins including transcription factors and otherprotein kinases, MEKs appear specific and sole activators of MAPKs andcould act as a focal point for cross-cascade regulation. MEK1 and MEK2isoforms show unusual specificity and also contain a proline-rich insertbetween catalytic subdomains IX and X which is not present in any of theother known MEK family members. These differences between MEK and otherprotein kinases, together with the known role of MEK (MEK 1, MEK 2) and,more recently MEK 5, in proliferative signalling suggest it may bepossible to discover and employ selective MEK inhibitors as therapeuticagents for use in proliferative disease.

Accordingly, it has been recognised that an inhibitor of the MAPK kinasepathway should be of value as an anti-proliferative agent for use in thecontainment and/or treatment of solid tumour disease.

It is also known that several oncogenes encode tyrosine kinase enzymesand that certain growth factor receptors are also tyrosine kinaseenzymes (Yarden et al., Ann. Rev. Biochem., 1988, 57, 443; Larsen etal., Ann. Reports in Med. Chem., 1989, Chpt. 13). The first group oftyrosine kinases to be identified arose from such viral oncogenes, forexample pp60^(v-Src) tyrosine kinase (otherwise known as v-Src), and thecorresponding tyrosine kinases in normal cells, for example pp60^(c-Src)tyrosine kinase (otherwise known as c-Src).

Receptor tyrosine kinases are important in the transmission ofbiochemical signals which initiate cell replication. Some of them arelarge enzymes which span the cell membrane and possess an extracellularbinding domain for growth factors such as epidermal growth factor (EGF)and an intracellular portion which functions as a kinase tophosphorylate tyrosine amino acids in proteins and hence to influencecell proliferation. Various classes of receptor tyrosine kinases areknown (Wilks, Advances in Cancer Research, 1993, 60, 43–73) based onfamilies of growth factors which bind to different receptor tyrosinekinases. The classification includes Class I receptor tyrosine kinasescomprising the EGF family of receptor tyrosine kinases such as the EGF,TGFα, Neu and erbB receptors, Class II receptor tyrosine kinasescomprising the insulin family of receptor tyrosine kinases such as theinsulin and IGFI receptors and insulin-related receptor (IRR) and ClassIII receptor tyrosine kinases comprising the platelet-derived growthfactor (PDGF) family of receptor tyrosine kinases such as the PDGFα,PDGFβ and colony-stimulating factor 1 (CSF1) receptors.

It is also known that certain tyrosine kinases belong to the class ofnon-receptor tyrosine kinases which are located intracellularly and areinvolved in the transmission of biochemical signals such as those thatinfluence tumour cell motility, dissemination and invasiveness andsubsequently metastatic tumour growth (Ullrich et al., Cell, 1990, 61,203–212, Bolen et al., FASEB J., 1992, 6, 3403–3409, Brickell et al.,Critical Reviews in Oncogenesis, 1992, 3, 401–406, Bohlen et al.,Oncogene, 1993, 8, 2025–2031, Courtneidge et al., Semin. Cancer Biol.,1994, 5, 239–246, Lauffenburger et al., Cell, 1996, 84, 359–369, Hankset al., BioEssays, 1996, 19, 137–145, Parsons et al., Current Opinion inCell Biology, 1997, 9, 187–192, Brown et al., Biochimica et BiophysicaActa, 1996, 1287, 121–149 and Schlaepfer et al., Progress in Biophysicsand Molecular Biology, 1999, 71, 435–478). Various classes ofnon-receptor tyrosine kinases are known including the Src family such asthe Src, Lyn and Yes tyrosine kinases, the Abl family such as Abl andArg and the Jak family such as Jak 1 and Tyk 2.

It is known that the Src family of non-receptor tyrosine kinases arehighly regulated in normal cells and in the absence of extracellularstimuli are maintained in an inactive conformation. However, some Srcfamily members, for example c-Src tyrosine kinase, are frequentlysignificantly activated (when compared to normal cell levels) in commonhuman cancers such as gastrointestinal cancer, for example colon, rectaland stomach cancer (Cartwright et al., Proc. Natl. Acad. Sci. USA, 1990,87, 558–562 and Mao et al., Oncogene, 1997, 15, 3083–3090), and breastcancer (Muthuswamy et al., Oncogene, 1995, 11, 1801–1810). The Srcfamily of non-receptor tyrosine kinases has also been located in othercommon human cancers such as non-small cell lung cancers (NSCLCs)including adenocarcinomas and squamous cell cancer of the lung(Mazurenko et al., European Journal of Cancer, 1992, 28, 372–7), bladdercancer (Fanning et al., Cancer Research, 1992, 52, 1457–62), oesophagealcancer (Jankowski et al., Gut, 1992, 33, 1033–8), cancer of theprostate, ovarian cancer (Wiener et al., Clin. Cancer Research, 1999, 5,2164–70) and pancreatic cancer (Lutz et al., Biochem. and Biophys. Res.Comm., 1998, 243, 503–8). As further human tumour tissues are tested forthe Src family of non-receptor tyrosine kinases it is expected that itswidespread prevalence will be, established.

It is further known that the predominant role of c-Src non-receptortyrosine kinase is to regulate the assembly of focal adhesion complexesthrough interaction with a number of cytoplasmic proteins including, forexample, focal adhesion kinase and paxillin. In addition c-Src iscoupled to signalling pathways that regulate the actin cytoskeletonwhich facilitates cell motility. Likewise, important roles are played bythe c-Src, c-Yes and c-Fyn non-receptor tyrosine kinases in integrinmediated signalling and in disrupting cadherin-dependent cell-celljunctions (Owens et al., Molecular Biology of the Cell, 2000, 11, 51–64and Klinghoffer et al., EMBO Journal, 1999, 18, 2459–2471). Cellularmotility is necessarily required for a localised tumour to progressthrough the stages of dissemination into the blood stream, invasion ofother tissues and initiation of metastatic tumour growth. For example,colon tumour progression from localised to disseminated, invasivemetastatic disease has been correlated with c-Src non-receptor tyrosinekinase activity (Brunton et al., Oncogene, 1997, 14, 283–293, Fincham etal., EMBO J, 1998, 17, 81–92 and Verbeek et al., Exp. Cell Research,1999, 248, 531–537).

Accordingly it has been recognised that an inhibitor of suchnon-receptor tyrosine kinases should be of value as a selectiveinhibitor of the motility of tumour cells and as a selective inhibitorof the dissemination and invasiveness of mammalian cancer cells leadingto inhibition of metastatic tumour growth. In particular an inhibitor ofsuch non-receptor tyrosine kinases should be of value as ananti-invasive agent for use in the containment and/or treatment of solidtumour disease.

We have now found that surprisingly certain quinoline derivativespossess potent anti-tumour activity. It is believed that the compoundsdisclosed in the present invention provide an anti-tumour effect by wayof inhibition of MEK enzymes that are involved in the MAPK kinasepathway and/or by way of inhibition of one or more of the non-receptortyrosine-specific protein kinases that are involved in the signaltransduction steps which lead to the invasiveness and migratory abilityof metastasising tumour cells. In particular, it is believed that thecompounds of the present invention provide an anti-tumour effect byinhibition of one or more of the MEK enzymes and/or by way of inhibitionof the Src family of non-receptor tyrosine kinases, for example byinhibition of one or more of c-Src, c-Yes and c-Fyn. It is also knownthat c-Src non-receptor tyrosine kinase enzyme is involved in thecontrol of osteoclast-driven bone resorption (Soriano et al., Cell,1991, 64, 693–702; Boyce et al., J. Clin. Invest., 1992, 90, 1622–1627;Yoneda et al., J. Clin. Invest., 1993, 91, 2791–2795 and Missbach etal., Bone, 1999, 24, 437–49). An inhibitor of c-Src non-receptortyrosine kinase is therefore of value in the prevention and treatment ofbone diseases such as osteoporosis, Paget's disease, metastatic diseasein bone and tumour-induced hypercalcaemia.

The compounds of the present invention are also useful in inhibiting theuncontrolled cellular proliferation which arises from variousnon-malignant diseases such as inflammatory diseases (for examplerheumatoid arthritis and inflammatory bowel disease), fibrotic diseases(for example hepatic cirrhosis and lung fibrosis), glomerulonephritis,multiple sclerosis, psoriasis, hypersensitivity reactions of the skin,blood vessel diseases (for example atherosclerosis and restenosis),allergic asthma, insulin-dependent diabetes, diabetic retinopathy anddiabetic nephropathy.

The compounds of the invention may possess inhibitory activity againstthe MEK enzymes that are involved in the MAPK kinase pathway. They mayalso possess an inhibitory activity against the Src family ofnon-receptor tyrosine kinases. Generally the compounds of the presentinvention may also possess potent inhibitory activity against the Srcfamily of non-receptor tyrosine kinases, for example by inhibition ofc-Src and/or c-Yes, whilst possessing less potent inhibitory activityagainst other tyrosine kinase enzymes such as the receptor tyrosinekinases, for example EGF receptor tyrosine kinase and/or VEGF receptortyrosine kinase.

It is stated in International Patent Application WO 98/43960 that arange of 3-cyanoquinoline derivatives are useful in the treatment ofcancer. Certain of the compounds are stated to be inhibitors of themitogen-activated protein kinase (MAPK) pathway, others are stated to beinhibitors of EGF receptor tyrosine kinase, and others are stated to beinhibitors of growth factors such as vascular endothelial growth factor(VEGF). There is no disclosure therein of any1,3-benzodioxol-4-yl-containing 3-cyanoquinoline derivatives.

It is stated in International Patent Application WO 00/68201 that arange of 3-cyanoquinoline derivatives are also useful in the treatmentof cancer. Certain of the compounds are stated to be inhibitors of MEK,a MAPK kinase. There is no disclosure therein of any1,3-benzodioxol-4-yl-containing 3-cyanoquinoline derivatives.

It is disclosed in Journal Medicinal Chemistry, 2001, 44, 822–833 thatcertain 4-anilino-3-cyanoquinoline derivatives are useful for theinhibition of Src-dependent cell proliferation. There is no disclosuretherein of any 1,3-benzodioxol-4-yl-containing 3-cyanoquinolinederivatives.

According to one aspect of the invention there is provided a quinolinederivative of the Formula I

wherein Z¹ is an O, S, SO, SO₂, N(R²) or C(R²)₂ group, wherein each R²group, which may be the same or different, is hydrogen or (1–6C)alkyl;

m is 0, 1, 2, 3 or 4;

each R¹ group, which may be the same or different, is selected fromhalogeno, trifluoromethyl, cyano, isocyano, nitro, hydroxy, mercapto,amino, formyl, carboxy, carbamoyl, (1–6C)alkyl, (2–8C)alkenyl,(2–8C)alkynyl, (1–6C)alkoxy, (2–6C)alkenyloxy, (2–6C)alkynyloxy,(1–6C)alkylthio, (1–6C)alkylsulphinyl, (1–6C)alkylsulphonyl,(1–6C)alkylamino, di-[(1–6C)alkyl]amino, (1–6C)alkoxycarbonyl,N-(1–6C)alkylcarbamoyl, N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl,(2–6C)alkanoyloxy, (2–6C)alkanoylamino,N-(1–6C)alkyl-(2–6C)alkanoylamino, (3–6C)alkenoylamino,N-(1–6C)alkyl-(3–6C)alkenoylamino, (3–6C)alkynoylamino,N-(1–6C)alkyl-(3–6C)alkynoylamino, N-(1–6C)alkylsulphamoyl,N,N-di-[(1–6C)alkyl]sulphamoyl, (1–6C)alkanesulphonylamino,N-(1–6C)alkyl-(1–6C)alkanesulphonylamino or from a group of the formula:Q¹-X¹—wherein X¹ is a direct bond or is selected from O, S, SO, SO₂, N(R⁴),CO, CH(OR¹), CON(R⁴), N(R⁴)CO, SO₂N(R⁴), N(R⁴)SO₂, OC(R⁴)₂, SC(R⁴)₂ andN(R⁴)C(R⁴)₂, wherein R⁴ is hydrogen or (1–6C)alkyl, and Q¹ is aryl,aryl-(1–6C)alkyl, (3–7C)cycloalkyl, (3–7C)cycloalkyl-(1–6C)alkyl,(3–7C)cycloalkenyl, (3–7C)cycloalkenyl-(1–6C)alkyl, heteroaryl,heteroaryl-(1–6C)alkyl, heterocyclyl or heterocyclyl-(1–6C)alkyl, or(R¹)_(m) is (1–3C)alkylenedioxy,

and wherein adjacent carbon atoms in any (2–6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, S, SO, SO₂, N(R⁵), CO, CH(OR⁵), CON(R⁵),N(R⁵)CO, SO₂N(R⁵), N(R⁵)SO₂, CH═CH and C≡C wherein R⁵ is hydrogen or(1–6C)alkyl or, when the inserted group is N(R⁵), R⁵ may also be(2–6C)alkanoyl,

and wherein any CH₂═CH— or HC≡C— group within a R¹ substituentoptionally bears at the terminal CH₂═ or HC≡ position a substituentselected from halogeno, carboxy, carbamoyl, (1–6C)alkoxycarbonyl,N-(1–6C)alkylcarbamoyl, N,N-di-[(1–6C)alkyl]carbamoyl,amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl,di-[(1–6C)alkyl]amino-(1–6C)alkyl or from a group of the formula:Q²-X²—wherein X² is a direct bond or is selected from CO and N(R⁶)CO, whereinR⁶ is hydrogen or (1–6C)alkyl, and Q² is aryl, aryl-(1–6C)alkyl,heteroaryl, heteroaryl-(1–6C)alkyl, heterocyclyl orheterocyclyl-(1–6C)alkyl,

and wherein any CH, CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH, CH₂ or CH₃ group one or more halogeno or(1–6C)alkyl substituents or a substituent selected from hydroxy, cyano,amino, carboxy, carbamoyl, (1–6C)alkoxy, 1–6C)alkylthio,(1–6C)alkylsulphinyl, (1–6C)alkylsulphonyl, (1–6C)alkylamino,N-[(1–6C)alkyl]amino, (1–6C)alkoxycarbonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl, (2–6C)alkanoyloxy,(2–6C)alkanoylamino, N-(1–6C)alkyl-(2–6C)alkanoylamino,N-(1–6C)alkylsulphamoyl, N,N-di-[(1–6C)alkyl]sulphamoyl,(1–6C)alkanesulphonylamino, N-(1–6C)alkyl-(1–6C)alkanesulphonylamino orfrom a group of the formula:—X³-Q³wherein X³ is a direct bond or is selected from O, S, SO, SO₂, N(R⁷),CO, CH(OR⁷), CON(R⁷), N(R⁷)CO, SO₂N(R⁷), N(R⁷)SO₂, C(R⁷)₂O, C(R⁷)₂S andN(R⁷)C(R⁷)₂, wherein R⁷ is hydrogen or (1–6C)alkyl, and Q³ is aryl,aryl-(1–6C)alkyl, (3–7C)cycloalkyl, (3–7C)cycloalkyl-(1–6C)alkyl,(3–7C)cycloalkenyl, (3–7C)cycloalkenyl-(1–6C)alkyl, heteroaryl,heteroaryl-(1–6C)alkyl, heterocyclyl or heterocyclyl-(1–6C)alkyl,

and wherein any aryl, heteroaryl or heterocyclyl group within asubstituent on R¹ optionally bears 1, 2 or 3 substituents, which may bethe same or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, carboxy, carbamoyl, (1–6C)alkyl, (2–8C)alkenyl,(2–8C)alkynyl, (1–6C)alkoxy, (2–6C)alkenyloxy, (2–6C)alkynyloxy,(1–6C)alkylthio, (1–6C)alkylsulphinyl, (1–6C)alkylsulphonyl,(1–6C)alkylamino, di-[(1–6C)alkyl]amino, (1–6C)alkoxycarbonyl,N-(1–6C)alkylcarbamoyl, N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl,(2–6C)alkanoyloxy, (2–6C)alkanoylamino,N-(1–6C)alkyl-(2–6C)alkanoylamino, N-(1–6C)alkylsulphamoyl,N,N-di-[(1–6C)alkyl]sulphamoyl, (1–6C)alkanesulphonylamino,N-(1–6C)alkyl-(1–6C)alkanesulphonylamino or from a group of the formula:—X⁴—R⁸wherein X⁴ is a direct bond or is selected from O and N(R⁹), wherein R⁹is hydrogen or (1–6C)alkyl, and R⁸ is halogeno-(1–6C)alkyl,hydroxy-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl,amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl,di-[(1–6C)alkyl]amino-(1–6C)alkyl, (2–6C)alkanoylamino-(1–6C)alkyl or(1–6C)alkoxycarbonylamino-(1–6C)alkyl or from a group of the formula:X⁵-Q⁴wherein X⁵ is a direct bond or is selected from O, N(R¹⁰) and CO,wherein R¹⁰ is hydrogen or (1–6C)alkyl, and Q⁴ is aryl,aryl-(1–6C)alkyl, heteroaryl, heteroaryl-(1–6C)alkyl, heterocyclyl orheterocyclyl-(1–6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1–6C)alkyl,(2–8C)alkenyl, (2–8C)alkynyl and (1–6C)alkoxy,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1 or 2 oxo or thioxo substituents;

5 n is 0, 1, 2 or 3;

each R³ group is halogeno, trifluoromethyl, cyano, nitro, hydroxy,amino, carboxy, carbamoyl, (1–6C)alkyl, (2–8C)alkenyl, (2–8C)alkynyl,(1–6C)alkoxy, (2–6C)alkenyloxy, (2–6C)alkynyloxy, (1–6C)alkylthio,(1–6C)alkylsulphinyl, (1–6C)alkylsulphonyl, (1–6C)alkylamino,di-[(1–6C)alkyl]amino, (1–6C)alkoxycarbonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl, (2–6C)alkanoyloxy,(2–6C)alkanoylamino, N-(1–6C)alkyl-(2–6C)alkanoylamino,(3–6C)alkenoylamino, N-(1–6C)alkyl-(3–6C)alkenoylamino,(3–6C)alkynoylamino, N-(1–6C)alkyl-(3–6C)alkynoylamino,N-(1–6C)alkylsulphamoyl, N,N-di-[(1–6C)alkyl]sulphamoyl,(1–6C)alkanesulphonylamino, N-(1–6C)alkyl-(1–6C)alkanesulphonylamino orfrom a group of the formula:—X⁶—R¹¹wherein X⁶ is a direct bond or is selected from O and N(R¹²), whereinR¹² is hydrogen or (1–6C)alkyl, and R¹¹ is halogeno-(1–6C)alkyl,hydroxy-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl,amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl ordi-[(1–6C)alkyl]amino-(1–6C)alkyl;

Z² is a C≡C or C(R¹³)═C(R¹³) group, wherein each R¹³ group, which may bethe same or different, is hydrogen or (1–6C)alkyl; and

R¹⁴ is selected from halogeno, cyano, isocyano, formyl, carboxy,carbamoyl, (2–8C)alkenyl, (2–8C)alkynyl, (1–6C)alkoxycarbonyl,N-(1–6C)alkylcarbamoyl, N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl,N-(1–6C)alkylsulphamoyl, N,N-di-[(1–6C)alkyl]sulphamoyl,halogeno-(1–6C)alkyl, hydroxy-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl,cyano-(1–6C)alkyl, amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl,di-[(1–6C)alkyl]amino-(1–6C)alkyl, (2–6C)alkanoylamino-(1–6C)alkyl,(1–6C)alkoxycarbonylamino-(1–6C)alkyl or from a group of the formula:—X⁷-Q⁵wherein X⁷ is a direct bond or is selected from CO, CH(OR¹⁵), CON(R⁵) orSO₂N(R¹⁵), wherein R¹⁵ is hydrogen or (1–6C)alkyl, and Q⁵ is aryl,aryl-(1–6C)alkyl, (3–7C)cycloalkyl, (3–7C)cycloalkyl-(1–6C)alkyl,heteroaryl, heteroaryl-(1–6C)alkyl, heterocyclyl orheterocyclyl-(1–6C)alkyl,

and wherein any CH, CH₂ or CH₃ group within a R¹⁴ substituent optionallybears on each said CH, CH₂ or CH₃ group one or more halogeno or(1–6C)alkyl substituents or a substituent selected from hydroxy, cyano,amino, carboxy, carbamoyl, (1–6C)alkoxy, (1–6C)alkylthio,(1–6C)alkylsulphinyl, (1–6C)alkylsulphonyl, (1–6C)alkylamino,di-[(1–6C)alkyl]amino, (1–6C)alkoxycarbonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl, (2–6C)alkanoyloxy,(2–6C)alkanoylamino, N-(1–6C)alkyl-(2–6C)alkanoylamino,N-(1–6C)alkylsulphamoyl, N,N-di-[(1–6C)alkyl]sulphamoyl,(1–6C)alkanesulphonylamino, N-(1–6C)alkyl-(1–6C)alkanesulphonylamino orfrom a group of the formula:—X⁸-Q⁶wherein X⁸ is a direct bond or is selected from O, S, SO, SO₂, N(R¹⁶),CO, CH(OR¹⁶), CON(R¹⁶), N(R¹⁶)CO, SO₂N(R¹⁶), N(R¹⁶)SO₂, C(R¹⁶)₂O,C(R¹⁶)₂S and N(R¹⁶)C(R¹⁶)₂, wherein R¹⁶ is hydrogen or (1–6C)alkyl, andQ⁶ is aryl, aryl-(1–6C)alkyl, (3–7C)cycloalkyl,(3–7C)cycloalkyl-(1–6C)alkyl, (3–7C)cycloalkenyl,(3–7C)cycloalkenyl-(1–6C)alkyl, heteroaryl, heteroaryl-(1–6C)alkyl,heterocyclyl or heterocyclyl-(1–6C)alkyl,

and wherein any aryl, heteroaryl or heterocyclyl group within asubstituent on R¹⁴ optionally bears 1, 2 or 3 substituents, which may bethe same or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, carboxy, carbamoyl, (1–6C)alkyl, (2–8C)alkenyl,(2–8C)alkynyl, (1–6C)alkoxy, (2–6C)alkenyloxy, (2–6C)alkynyloxy,(1–6C)alkylthio, (1–6C)alkylsulphinyl, (1–6C)alkylsulphonyl,(1–6C)alkylamino, di-[(1–6C)alkyl]amino, (1–6C)alkoxycarbonyl,N-(1–6C)alkylcarbamoyl, N,N-1-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl,(2–6C)alkanoyloxy, (2–6C)alkanoylamino,N-(1–6C)alkyl-(2–6C)alkanoylamino, N-(1–6C)alkylsulphamoyl,N,N-di-[(1–6C)alkyl]sulphamoyl, (1–6C)alkanesulphonylamino,N-(1–6C)alkyl-(1–6C)alkanesulphonylamino or from a group of the formula:—X⁹—R¹⁷wherein X⁹ is a direct bond or is selected from O and N(R¹⁸), whereinR¹⁸ is hydrogen or (1–6C)alkyl, and R¹⁷ is halogeno-(1–6C)alkyl,hydroxy-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl,amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl,di-[(1–6C)alkyl]amino-(1–6C)alkyl, (2–6C)alkanoylamino-(1–6C)alkyl,(1–6C)alkoxycarbonylamino-(1–6C)alkyl, or from a group of the formula:—X¹⁰-Q⁷wherein X¹⁰ is a direct bond or is selected from O, N(R¹⁹) and CO,wherein R¹⁹ is hydrogen or (1–6C)alkyl, and Q⁷ is aryl,aryl-(1–6C)alkyl, heteroaryl, heteroaryl-(1–6C)alkyl, heterocyclyl orheterocyclyl-(1–6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1–6C)alkyl,(2–8C)alkenyl, (2–8C)alkynyl and (1–6C)alkoxy,

and wherein any heterocyclyl group within a substituent on R¹⁴optionally bears 1 or 2 oxo or thioxo substituents;

or a pharmaceutically-acceptable salt thereof.

In this specification the generic term “alkyl” includes bothstraight-chain and branched-chain alkyl groups such as propyl, isopropyland tert-butyl, and also (3–7C)cycloalkyl groups such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. However referencesto individual alkyl groups such as “propyl” are specific for thestraight-chain version only, references to individual branched-chainalkyl groups such as “isopropyl” are specific for the branched-chainversion only and references to individual cycloalkyl groups such as“cyclopentyl” are specific for that 5-membered ring only. An analogousconvention applies to other generic terms, for example (1–6C)alkoxyincludes methoxy, ethoxy, cyclopropyloxy and cyclopentyloxy,(1–6C)alkylamino includes methylamino, ethylamino, cyclobutylamino andcyclohexylamino, and di-[(1–6C)alkyl]amino includes dimethylamino,diethylamino, N-cyclobutyl-N-methylamino and N-cyclohexyl-N-ethylamino.

It is to be understood that, insofar as certain of the compounds ofFormula I defined above may exist in optically active or racemic formsby virtue of one or more asymmetric carbon atoms, the invention includesin its definition any such optically active or racemic form whichpossesses the above-mentioned activity. The synthesis of opticallyactive forms may be carried out by standard techniques of organicchemistry well known in the art, for example by synthesis from opticallyactive starting materials or by resolution of a racemic form. Similarly,the above-mentioned activity may be evaluated using the standardlaboratory techniques referred to hereinafter.

Suitable values for the generic radicals referred to above include thoseset out below.

A suitable value for any one of the ‘Q’ groups (Q¹ to Q⁷) when it isaryl or for the aryl group within a ‘Q’ group is, for example, phenyl ornaphthyl, preferably phenyl.

A suitable value for any one of the ‘Q’ groups (Q¹, Q³, Q⁵ or Q⁶) whenit is (3–7C)cycloalkyl or for the (3–7C)cycloalkyl group within a ‘Q’group is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or bicyclo[2.2.1]heptyl and a suitable value for any one ofthe ‘Q’ groups (Q¹, Q³ or Q⁶) when it is (3–7C)cycloalkenyl or for the(3–7C)cycloalkenyl group within a ‘Q’ group is, for example,cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.

A suitable value for any one of the ‘Q’ groups (Q¹ to Q⁷) when it isheteroaryl or for the heteroaryl group within a ‘Q’ group is, forexample, an aromatic 5- or 6-membered monocyclic ring or a 9- or10-membered bicyclic ring with up to five ring heteroatoms selected fromoxygen, nitrogen and sulphur, for example furyl, pyrrolyl, thienyl,oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl,benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl,benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl,cinnolinyl or naphthyridinyl.

A suitable value for any one of the ‘Q’ groups (Q¹ to Q⁷) when it isheterocyclyl or for the heterocyclyl group within a ‘Q’ group is, forexample, a non-aromatic saturated or partially saturated 3 to 10membered monocyclic or bicyclic ring with up to five heteroatomsselected from oxygen, nitrogen and sulphur, for example oxiranyl,oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl,tetrahydrothienyl, 1,1-dioxotetrahydrothienyl, tetrahydrothiopyranyl,1,1-dioxotetrahydrothiopyranyl, azetidinyl, pyrrolinyl, pyrrolidinyl,morpholinyl, tetrahydro-1,4-thiazinyl,1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl,piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl,dihydropyrimidinyl or tetrahydropyrimidinyl, preferablytetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl,1,1-dioxotetrahydro-4H-1,4-thiazinyl, piperidinyl or piperazinyl. Asuitable value for such a group which bears 1 or 2 oxo or thioxosubstituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl,2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl,2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.

A suitable value for a ‘Q’ group when it is heteroaryl-(1–6C)alkyl is,for example, heteroarylmethyl, 2-heteroarylethyl and 3-heteroarylpropyl.The invention comprises corresponding suitable values for ‘Q’ groupswhen, for example, rather than a heteroaryl-(1–6C)alkyl group, anaryl-(1–6C)alkyl, (3–7C)cycloalkyl-(1–6C)alkyl,(3–7C)cycloalkenyl-(1–6C)alkyl or heterocyclyl-(1–6C)alkyl group ispresent.

A suitable value for a ‘Q’ group when it is heterocyclyl-(1–6C)alkyl is,for example, 3-piperazin-1-ylpropyl, 3-morpholinopropyl,3-(1,1-dioxotetrahydro-4H-1,4-thiazinyl)propyl, 3-piperidin-4-ylpropyl,3-piperidin-1-ylpropyl or 4-pyrrolidin-1ylbutyl.

In structural Formula I there is a hydrogen atom at the 2-position onthe quinoline ring. It is to be understood thereby that the R¹substituents may only be located at the 5-, 6-, 7- or 8-positions on thequinoline ring i.e. that the 2-position remains unsubstituted. It isfurther to be understood that the R³ group that may be present on the1,3-benzodioxol-4-yl group within structural Formula I may be located onthe phenyl ring or on the methylene group within the dioxol group.Preferably, any R³ group that is present on the 1,3-benzodioxol-4-ylgroup within structural Formula I is located on the phenyl ring thereof.It is further to be understood that the -Z²-R¹⁴ group within structuralFormula I may only be located on the phenyl ring within the1,3-benzodioxol-4-yl group.

For the avoidance of doubt, the positions on structural Formula I arenumbered as follows:

Suitable values for any of the ‘R’ groups (R¹ to R¹⁹) or for variousgroups within an R¹, R³ or R⁴ group include:

-   for halogeno fluoro, chloro, bromo and iodo;-   for (1–6C)alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl;-   for (2–8C)alkenyl: vinyl, isopropenyl, allyl and but-2-enyl;-   for (2–8C)alkynyl: ethynyl, 2-propynyl and but-2-ynyl;-   for (1–6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy;-   for (2–6C)alkenyloxy: vinyloxy and allyloxy;-   for (2–6C)alkynyloxy: ethynyloxy and 2-propynyloxy;-   for (1–6C)alkylthio: methylthio, ethylthio and propylthio;-   for (1–6C)alkylsulphonyl: methylsulphinyl and ethylsulphinyl;-   for (1–6C)alkylsulphonyl: methylsulphonyl and ethylsulphonyl;-   for (1–6C)alkylamino: methylamino, ethylamino, propylamino,    isopropylamino and butylamino;-   for di-[(1–6C)alkyl]amino: dimethylamino, diethylamino,    N-ethyl-N-methylamino and diisopropylamino;-   for (1–6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl,    propoxycarbonyl and tert-butoxycarbonyl;-   for N-(1–6C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl and    N-propylcarbamoyl;-   for N,N-di-[(1–6C)alkyl]carbamoyl: N,N-dimethylcarbamoyl,    N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl;-   for (2–6C)alkanoyl: acetyl and propionyl;-   for (2–6C)alkanoyloxy: acetoxy and propionyloxy;-   for (2–6C)alkanoylamino: acetamido and propionamido;-   for N-(1–6C)alkyl-(2–6C)alkanoylamino: N-methylacetamido and    N-methylpropionamido;-   for N-(1–6C)alkylsulphamoyl: N-methylsulphamoyl and    N-ethylsulphamoyl;-   for N,N-di-[(1–6C)alkyl]sulphamoyl: N,N-dimethylsulphamoyl;-   for (1–6C)alkanesulphonylamino: methanesulphonylamino and    ethanesulphonylamino;-   for N-(1–6C)alkyl-(1–6C)alkanesulphonylamino:    N-methylmethanesulphonylamino and N-methylethanesulphonylamino;-   for (3–6C)alkenoylamino: acrylamido, methacrylamido and crotonamido;-   for N-(1–6C)alkyl-(3–6C)alkenoylamino: N-methylacrylamido and    N-methylcrotonamido;-   for (3–6C)alkynoylamino: propiolamido;-   for N-(1–6C)alkyl-(3–6C)alkynoylamino: N-methylpropiolamido;-   for amino-(1–6C)alkyl: aminomethyl, 2-aminoethyl, 1-aminoethyl and    3-aminopropyl;-   for (1–6C)alkylamino-(1–6C)alkyl: methylaminomethyl,    ethylaminomethyl, 1-methylaminoethyl, 2-methylaminoethyl,-   2-ethylaminoethyl and 3-methylaminopropyl;-   for di-[(1–6C)alkyl]amino-(1–6C)alkyl: dimethylaminomethyl,    diethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and    3-dimethylaminopropyl;-   for halogeno-(1–6C)alkyl: chloromethyl, 2-chloroethyl, 1-chloroethyl    and 3-chloropropyl;-   for hydroxy-(1–6C)alkyl: hydroxymethyl, 2-hydroxyethyl,    1-hydroxyethyl and 3-hydroxypropyl;-   for (1–6C)alkoxy-(1–6C)alkyl: methoxymethyl, ethoxymethyl,    1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl;-   for cyano-(1–6C)alkyl: cyanomethyl, 2-cyanoethyl, 1-cyanoethyl and    3-cyanopropyl;-   for (2–6C)alkanoylamino-(1–6C)alkyl: acetamidomethyl,    propionamidomethyl and 2-acetamidoethyl; and-   for (1–6C)alkoxycarbonylamino-(1–6C)alkyl:    methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl,    tert-butoxycarbonylaminomethyl and 2-methoxycarbonylaminoethyl.

A suitable value for (R¹)_(m) when it is a (1–3C)alkylenedioxy group is,for example, methylenedioxy or ethylenedioxy and the oxygen atomsthereof occupy adjacent ring positions.

When, as defined hereinbefore, an R¹ group forms a group of the formulaQ¹-X¹— and, for example, X¹ is a OC(R⁴)₂ linking group, it is the carbonatom, not the oxygen atom, of the OC(R⁴)₂ linking group which isattached to the quinoline ring and the oxygen atom is attached to the Q¹group. Similarly, when, for example a CH₃ group within a R¹ substituentbears a group of the formula —X³-Q³ and, for example, X³ is a C(R⁷)₂Olinking group, it is the carbon atom, not the oxygen atom, of theC(R⁷)₂O linking group which is attached to the CH₃ group and the oxygenatom is linked to the Q³ group. A similar convention applies to theattachment of the groups of the formulae Q³-X³—, and —X⁸-Q⁶.

As defined hereinbefore, adjacent carbon atoms in any (2–6C)alkylenechain within a R¹ substituent may be optionally separated by theinsertion into the chain of a group such as O, CON(R⁵) or C≡C. Forexample, insertion of a C≡C group into the ethylene chain within a2-morpholinoethoxy group gives rise to a 4-morpholinobut-2-ynyloxy groupand, for example, insertion of a CONH group into the ethylene chainwithin a 3-methoxypropoxy group gives rise to, for example, a2-(2-methoxyacetamido)ethoxy group.

When, as defined hereinbefore, any CH, CH₂ or CH₃ group within a R¹ orR¹⁴ substituent optionally bears on each said CH, CH₂ or CH₃ group asubstituent as defined hereinbefore, suitable R¹ or R¹⁴ substituents soformed include, for example, hydroxy-substitutedheterocyclyl-(1–6C)alkoxy groups such as 2-hydroxy-3-piperidinopropoxyand 2-hydroxy-3-morpholinopropoxy.

A suitable pharmaceutically-acceptable salt of a compound of the FormulaI is, for example, an acid-addition salt of a compound of the Formula I,for example an acid-addition salt with an inorganic or organic acid suchas hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric ormaleic acid; or, for example, a salt of a compound of the Formula Iwhich is sufficiently acidic, for example an alkali or alkaline earthmetal salt such as a calcium or magnesium salt, or an ammonium salt, ora salt with an organic base such as methylamine, dimethylamine,trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

Particular novel compounds of the invention include, for example,quinoline derivatives of the Formula I, or pharmaceutically-acceptablesalts thereof, wherein, unless otherwise stated, each of Z¹, m, R¹, n,R³, Z² and R¹⁴ has any of the meanings defined hereinbefore or inparagraphs (a) to (y) hereinafter:—

-   (a) Z¹ is O, S, SO, SO₂, CH₂ or NH;-   (b) Z¹ is O;-   (c) Z¹ is NH;-   (d) R¹ substituents may only be located at the 5-, 6- and/or    7-positions on the quinoline ring i.e. the 2- and 8-positions remain    unsubstituted;-   (e) R¹ substituents may only be located at the 6- and/or 7-positions    on the quinoline ring i.e. the 2-, 5- and 8-positions remain    unsubstituted;-   (f) R¹ substituents may only be located at the 5- and/or 7-positions    on the quinoline ring i.e. the 2-, 6- and 8-positions remain    unsubstituted;-   (g) m is 1 or 2, and each R¹ group, which may be the same or    different, is selected from halogeno, trifluoromethyl, hydroxy,    amino, carbamoyl, (1–6C)alkyl, (2–8C)alkenyl, (2–8C)alkynyl,    (1–6C)alkoxy, (2–6C)alkenyloxy, (2–6C)alkyloxy, (1–6C)alkylamino,    di-[(1–6C)alkyl]amino, N-(1–6C)alkylcarbamoyl,    N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoylamino,    N-(1–6C)alkyl-(2–6C)alkanoylamino, (3–6C)alkenoylamino,    N-(1–6C)alkyl-(3–6C)alkenoylamino, (3–6C)alkynoylamino and    N-(1–6C)alkyl-(3–6C)alkynoylamino or from a group of the formula:    Q¹-X¹—    wherein X¹ is a direct bond or is selected from O, N(R⁴), CON(R⁴),    N(R⁴)CO and OC(R⁴)₂ wherein R⁴ is hydrogen or (1–6C)alkyl, and Q¹ is    aryl, aryl-(1–6C)alkyl, cycloalkyl-(1–6C)alkyl, heteroaryl,    heteroaryl-(1–6C)alkyl, heterocyclyl or heterocyclyl-(1–6C)alkyl,

and wherein adjacent carbon atoms in any (2–6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, N(R⁵), CON(R⁵), N(R⁵)CO, CH—CH and C≡Cwherein R⁵ is hydrogen or (1–6C)alkyl, or, when the inserted group isN(R⁵), R⁵ may also be (2–6C)alkanoyl,

and wherein any CH₂═CH— or HC≡C— group within a R¹ substituentoptionally bears at the terminal CH₂═ or HC≡ position a substituentselected from carbamoyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, amino-(1–6C)alkyl,(1–6C)alkylamino-(1–6C)alkyl and di-[(1–6C)alkyl]amino-(1–6C)alkyl orfrom a group of the formula:Q²-X²—wherein X² is a direct bond or is CO or N(R⁶)CO, wherein R⁶ is hydrogenor (1–6C)alkyl, and Q² is heteroaryl, heteroaryl-(1–6C)alkyl,heterocyclyl or heterocyclyl-(1–6C)alkyl,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more halogeno groups or asubstituent selected from hydroxy, amino, (1–6C)alkoxy,(1–6C)alkylsulphonyl, (1–6C)alkylamino, di-[(1–6C)alkyl]amino,(2–6C)alkanoyloxy, (2–6C)alkanoylamino,N-(1–6C)alkyl-(2–6C)alkanoylamino or from a group of the formula:—X³-Q³wherein X³ is a direct bond or is selected from O, N(R⁶), CON(R⁷),N(R⁷)CO and C(R⁷)₂O, wherein R⁷ is hydrogen or (1–6C)alkyl, and Q³ isheteroaryl, heteroaryl-(1–6C)alkyl, heterocyclyl orheterocyclyl-(1–6C)alkyl,

and wherein any aryl, heteroaryl or heterocyclyl group within asubstituent on R¹ optionally bears 1, 2 or 3 substituents, which may bethe same or different, selected from halogeno, trifluoromethyl, hydroxy,amino, carbamoyl, (1–6C)alkyl, (2–8C)alkenyl, (2–8C)alkyl, (1–6C)alkoxy,(1–6C)alkylsulphonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl and (2–6C)alkanoyl, or optionally bears 1substituent selected from a group of the formula:—X⁴—R⁸wherein X⁴ is a direct bond or is selected from O and N(R⁹), wherein R⁹is hydrogen or (1–6C)alkyl, and R⁸ is halogeno-(1–6C)alkyl,hydroxy-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl,amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl,di-[(1–6C)alkyl]amino-(1–6C)alkyl, (2–6C)alkanoylamino-(1–6C)alkyl,(1–6C)alkoxycarbonylamino-(1–6C)alkyl or from a group of the formula:—X⁵-Q⁴wherein X⁵ is a direct bond or is selected from O, N(R¹⁰) and CO,wherein R¹⁰ is hydrogen or (1–6C)alkyl, and Q⁴ is heterocyclyl orheterocyclyl-(1–6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1–6C)alkyland (1–6C)alkoxy,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1 or 2 oxo substituents;

-   (h) m is 1 or 2, and each R¹ group, which may be the same or    different, is selected from fluoro, chloro, trifluoromethyl,    hydroxy, amino, carbamoyl, methyl, ethyl, propyl, butyl, vinyl,    allyl, but-3-enyl, pent-4-enyl, hex-5-enyl, ethynyl, 2-propynyl,    but-3-ynyl, pent-4-ynyl, hex-5-ynyl, methoxy, ethoxy, propoxy;    isopropoxy, butoxy, allyloxy, but-3-enyloxy, pent-4-enyloxy,    hex-5-enyloxy, ethynyloxy, 2-propynyloxy, but-3-ynyloxy,    pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, propylamino,    dimethylamino, diethylamino, dipropylamino, N-methylcarbamoyl,    N,N-dimethylcarbamoyl, acetamido, propionamido, acrylamido and    propiolamido or from a group of the formula:    Q¹-X¹—    wherein X¹ is a direct bond or is selected from O, NH, CONH, NHCO    and OCH₂ and Q¹ is phenyl, benzyl, cyclopropylmethyl, 2-thienyl,    1-imidazolyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 2-, 3- or    4-pyridyl, 2-imidazol-1-ylethyl, 3-imidazol-1-ylpropyl,    2-(1,2,3-triazolyl)ethyl, 3-(1,2,3-triazolyl)propyl,    2-(1,2,4-triazolyl)ethyl, 3-(1,2,4-triazolyl)propyl, 2-, 3- or    4-pyridylmethyl, 2-(2-, 3- or 4-pyridyl)ethyl, 3-(2-, 3- or    4-pyridyl)propyl, tetrahydrofuran-3-yl, 3- or 4-tetrahydropyranyl,    1-, 2- or 3-pyrrolidinyl, morpholino,    1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, piperidino, piperidin-3-yl,    piperidin-4-yl, 1-, 3- or 4-homopiperidinyl, piperazin-1-yl,    homopiperazin-1-yl, 1-, 2- or 3-pyrrolidinylmethyl,    morpholinomethyl, piperidinomethyl, 3- or 4-piperidinylmethyl, 1-,    3- or 4-homopiperidinylmethyl, 2-pyrrolidin-1-ylethyl,    3-pyrrolidin-2-ylpropyl, pyrrolidin-2-ylmethyl,    2-pyrrolidin-2-ylethyl, 3-pyrrolidin-1-ylpropyl,    4-pyrrolidin-1-ylbutyl, 2-morpholinoethyl, 3-morpholinopropyl,    4-morpholinobutyl, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethyl,    3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propyl,    2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl,    2-piperidin-3-ylethyl, 3-piperidin-3-ylpropyl,    2-piperidin-4-ylethyl, 3-piperidin-4-ylpropyl,    2-homopiperidin-1-ylethyl, 3-homopiperidin-1-ylpropyl,    2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl,    4-piperazin-1-ylbutyl, 2-homopiperazin-1-ylethyl or    3-homopiperazin-1-ylpropyl,

and wherein adjacent carbon atoms in any (2–6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, NH, N(Me), CONH, NHCO, CH═CH and C≡C,

and wherein any CH₂═CH— or HC≡C— group within a R¹ substituentoptionally bears at the terminal CH₂═ or HC≡ position a substituentselected from carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl,N-propylcarbamoyl, N,N-dimethylcarbamoyl, aminomethyl, 2-aminoethyl,3-aminopropyl, 4-aminobutyl, methylaminomethyl, 2-methylaminoethyl,3-methylaminopropyl, 4-methylaminobutyl, dimethylaminomethyl,2-dimethylaminoethyl 3-dimethylaminopropyl or 4-dimethylaminobutyl, orfrom a group of the formula:Q²-X²wherein X² is a direct bond or is CO, NHCO or N(Me)CO and Q² is pyridyl,pyridylmethyl, 2-pyridylethyl, pyrrolidin-1-yl, pyrrolidin-2-yl,morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl,pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl,4-pyrrolidin-1-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl,3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl,3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl,2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl,piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl,2-piperidin-4-ylethyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl,3-piperazin-1-ylpropyl or 4-piperazin-1-ylbutyl,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more fluoro or chloro groupsor a substituent selected from hydroxy, amino, methoxy, methylsulphonyl,methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino,N-isopropyl-N-methylamino, N-methyl-N-propylamino, acetoxy, acetamidoand N-methylacetamido or from a group of the formula:—X³-Q³wherein X³ is a direct bond or is selected from O, NH, CONH, NHCO andCH₂O and Q³ is pyridyl, pyridylmethyl, pyrrolidin-1-yl, pyrrolidin-2-yl,morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl,2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, pyrrolidin-2-ylmethyl,2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl,3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl,2-piperidin-4-ylethyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl,

and wherein any aryl, heteroaryl or heterocyclyl group within asubstituent on R¹ optionally bears 1, 2 or 3 substituents, which may bethe same or different, selected from fluoro, chloro, trifluoromethyl,hydroxy, amino, carbamoyl, methyl, ethyl, allyl, 2-propynyl, methoxy,methylsulphonyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl and acetyl oroptionally bears 1 substituent selected from a group of the formula:—X⁴—R⁸wherein X⁴ is a direct bond or is selected from O and NH and R⁸ is2-fluoroethyl, 3-fluoropropyl, 2-hydroxyethyl, 3-hydroxypropyl,2-methoxyethyl, 3-methoxypropyl, cyanomethyl, aminomethyl, 2-aminoethyl,3-aminopropyl, methylaminomethyl, 2-methylaminoethyl,3-methylaminopropyl, 2-ethylaminoethyl, 3-ethylaminopropyl,dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl,acetamidomethyl, methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl,tert-butoxycarbonylaminomethyl or a group of the formula:—X⁵-Q⁴wherein X⁵ is a direct bond or is selected from O, NH and CO and Q⁴ ispyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl,morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl,piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl,piperazin-1-ylmethyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl,each of which optionally bears 1 or 2 substituents, which may be thesame or different, selected from fluoro, chloro, methyl and methoxy,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1 or 2 oxo substituents;

-   (i) m is 1 or 2, and each R¹ group, which may be the same or    different, is selected from halogeno, trifluoromethyl, hydroxy,    amino, carbamoyl, (1–6C)alkyl, (1–6C)alkoxy, (1–6C)alkylamino,    di-[(1–6C)alkyl]amino, N-(1–6C)alkylcarbamoyl,    N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoylamino,    N-(1–6C)alkyl-(2–6C)alkanoylamino or from a group of the formula:    Q¹-X¹—    wherein X¹ is selected from O, —N(R⁴), CON(R⁴), N(R⁴)CO and OC(R⁴)₂    wherein R⁴ is hydrogen or (1–6C)alkyl, and Q¹ is aryl,    aryl-(1–6C)alkyl, cycloalkyl-(1–6C)alkyl, heteroaryl,    heteroaryl-(1–6C)alkyl, heterocyclyl or heterocyclyl-(1–6C)alkyl, or    X¹ is a direct bond and Q¹ is aryl-(1–6C)alkyl,    cycloalkyl-(1–6C)alkyl, heteroaryl-(1–6C)alkyl or    heterocyclyl-(1–6C)alkyl,

and wherein adjacent carbon atoms in any (2–6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, N(R⁵), CON(R⁵), N(R⁵)CO, CH═CH and C≡Cwherein R⁵ is hydrogen or (1–6C)alkyl, or, when the inserted group isN(R⁵), R⁵ may also be (2–6C)alkanoyl,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more halogeno groups or asubstituent-selected from hydroxy, amino, (1–6C)alkoxy,(1–6C)alkylsulphonyl, (1–6C)alkylamino, di [(1–6C)alkyl]amino,(2–6C)alkanoyloxy, (2–6C)alkanoylamino,N-(1–6C)alkyl-(2–6C)alkanoylamino or a group of the formula:—X³-Q³wherein X³ is a direct bond or is selected from O, N(R⁶), CON(R⁷),N(R⁷)CO and C(R⁷)₂O, wherein R⁷ is hydrogen or (1–6C)alkyl, and Q³ isheteroaryl, heteroaryl-(1–6C)alkyl, heterocyclyl orheterocyclyl-(1–6C)alkyl,

and wherein any aryl, heteroaryl or heterocyclyl group within asubstituent on R¹ optionally bears 1, 2 or 3 substituents, which may bethe same or different, selected from halogeno, trifluoromethyl, hydroxy,amino, carbamoyl, (1–6C)alkyl, (2–8C)alkenyl, (2–8C)alkynyl,(1–6C)alkoxy, (1–6C)alkylsulphonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl and (2–6C)alkanoyl, or optionally bears 1substituent selected from a group of the formula:—X⁴—R⁸wherein X⁴ is a direct bond or is selected from O and N(R⁹), wherein R⁹is hydrogen or (1–6C)alkyl, and R⁸ is hydroxy-(1–6C)alkyl,(1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl, amino-(1–6C)alkyl,(1–6C)alkylamino-(1–6C)alkyl, di-[(1–6C)alkyl]amino-(1–6C)alkyl,(2–6C)alkanoylamino-(1–6C)alkyl, (1–6C)alkoxycarbonylamino-(1–6C)alkylor from a group of the formula:—X⁵-Q⁴wherein X⁵ is a direct bond or is selected from O, N(R¹⁰) and CO,wherein R¹⁰ is hydrogen or (1–6C)alkyl, and Q⁴ is heterocyclyl orheterocyclyl-(1–6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1–6C)alkyland (1–6C)alkoxy,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1 or 2 oxo substituents;

-   (j) m is 1 or 2, and each R¹ group, which may be the same or    different, is selected from fluoro, chloro, trifluoromethyl,    hydroxy, amino, carbamoyl, methyl, ethyl, propyl, butyl, methoxy,    ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino,    propylamino, dimethylamino, diethylamino, dipropylamino,    N-methylcarbamoyl, N,N-dimethylcarbamoyl, acetamido, propionamido,    acrylamido, propiolamido or from a group of the formula:    Q¹-X¹—    wherein X¹ is selected from O, NH, CONH, NHCO and OCH₂ and Q¹ is    phenyl, benzyl, cyclopropylmethyl, 2-thienyl, 1-imidazolyl,    1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 2-, 3- or 4-pyridyl,    2-imidazol-1-ylethyl, 3-imidazol-1-ylpropyl,    2-(1,2,3-triazolyl)ethyl, 3-(1,2,3-triazolyl)propyl,    2-(1,2,4-triazolyl)ethyl, 3-(1,2,4-triazolyl)propyl, 2-, 3- or    4-pyridylmethyl, 2-(2-, 3- or 4-pyridyl)ethyl, 3-(2-, 3- or    4-pyridyl)propyl, tetrahydrofuran-3-yl, 3- or 4-tetrahydropyranyl,    1-, 2- or 3-pyrrolidinyl, morpholino,    1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, piperidino, piperidin-3-yl,    piperidin-4-yl, 1-, 3- or 4-homopiperidinyl, piperazin-1-yl,    homopiperazin-1-yl, 1-, 2- or 3-pyrrolidinylmethyl,    morpholinomethyl, piperidinomethyl, 3- or 4-piperidinomethyl, 1-, 3-    or 4-homopiperidinylmethyl, 2-pyrrolidin-1-ylethyl,    3-pyrrolidin-2-ylpropyl, pyrrolidin-2-ylmethyl,    2-pyrrolidin-2-ylethyl, 3-pyrrolidin-1-ylpropyl,    4-pyrrolidin-1-ylbutyl, 2-morpholinoethyl, 3-morpholinopropyl,    4-morpholinobutyl, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethyl,    3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propyl,    2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl,    2-piperidin-3-ylethyl, 3-piperidin-3-ylpropyl,    2-piperidin-4-ylethyl, 3-piperidin-4-ylpropyl,    2-homopiperidin-1-ylethyl, 3-homopiperidin-1-ylpropyl,    2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl,    4-piperazin-1-ylbutyl, 2-homopiperazin-1-ylethyl or    3-homopiperazin-1-ylpropyl,    or wherein X¹ is a direct bond and Q¹ is benzyl, cyclopropylmethyl,    2-imidazol-1-ylethyl, 3-imidazol-1-ylpropyl,    2-(1,2,3-triazolyl)ethyl, 3-(1,2,3-triazolyl)propyl,    2-(1,2,4-triazolyl)ethyl, 3-(1,2,4-triazolyl)propyl, 2-, 3- or    4-pyridylmethyl, 2-(2-, 3- or 4-pyridyl)ethyl, 3-(2-, 3- or    4-pyridyl)propyl, 1-, 2- or 3-pyrrolidinylmethyl, morpholinomethyl,    piperidinomethyl, 3- or 4-piperidinylmethyl, 1-, 3- or    4-homopiperidinylmethyl, 2-pyrrolidin-1-ylethyl,    3-pyrrolidin-2-ylpropyl, pyrrolidin-2-ylmethyl,    2-pyrrolidin-2-ylethyl, 3-pyrrolidin-1-ylpropyl,    4-pyrrolidin-1-ylbutyl, 2-morpholinoethyl, 3-morpholinopropyl,    4-morpholinobutyl, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethyl,    3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propyl,    2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl,    2-piperidin-3-ylethyl, 3-piperidin-3-ylpropyl,    2-piperidin-4-ylethyl, 3-piperidin-4-ylpropyl,    2-homopiperidin-1-ylethyl, 3-homopiperidin-1-ylpropyl,    2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl,    4-piperazin-1-ylbutyl, 2-homopiperazin-1-ylethyl or    3-homopiperazin-1-ylpropyl,

and wherein adjacent carbon atoms in any (2–6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, NH, is N(Me), CONH, NHCO, CH═CH and C≡C,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more fluoro or chloro groupsor a substituent selected from hydroxy, amino, methoxy, methylsulphonyl,methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino,N-isopropyl-N-methylamino, N-methyl-N-propylamino, acetoxy, acetamido,N-methylacetamido or from a group of the formula:—X³-Q³wherein X³ is a direct bond or is selected from O, NH, CONH, NHCO andCH₂O and Q³ is pyridyl, pyridylmethyl, pyrrolidin-1-yl, pyrrolidin-2-yl,morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl,2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, pyrrolidin-2-ylmethyl,2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl,3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropylpiperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl,2-piperidin-4-ylethyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl,

and wherein any aryl, heteroaryl or heterocyclyl group within asubstituent on R¹ optionally bears 1, 2 or 3 substituents, which may bethe same or different, selected from fluoro, chloro, trifluoromethyl,hydroxy, amino, carbamoyl, methyl, ethyl, allyl, 2-propynyl, methoxy,methylsulphonyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl and acetyl, oroptionally bears 1 substituent selected from a group of the formula:—X⁴—R⁸wherein X⁴ is a direct bond or is selected from O and NH and R⁸ is2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl,cyanomethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl,methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl2-ethylaminoethyl, 3-ethylaminopropyl, dimethylaminomethyl,2-dimethylaminoethyl, 3-dimethylaminopropyl, acetamidomethyl,methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl,tert-butoxycarbonylaminomethyl or from a group of the formula:—X⁵-Q⁴wherein X⁵ is a direct bond or is selected from O, NH and CO and Q⁴ ispyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl,morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl,piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl,piperazin-1-ylmethyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl,each of which optionally bears 1 or 2 substituents, which may be thesame or different, selected from fluoro, chloro, methyl and methoxy,and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1 or 2 oxo substituents;

-   (k) m is 2 and each R¹ group, which may be the same or different, is    located at the 5- and 7-positions or at the 6- and 7-positions and    R¹ is selected from hydroxy, amino, methyl, ethyl, propyl, methoxy,    ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, methylamino,    ethylamino, dimethylamino, diethylamino, acetamido, propionamido,    cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy,    tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,    tetrahydropyran-4-yloxy, cyclopropylmethoxy, 2-imidazol-1-ylethoxy,    3-imidazol-1-ylpropoxy, 2-(1,2,3-triazol-1-yl)ethoxy,    3-(1,2,3-triazol-1-yl)propoxy, 2-(1,2,4-triazol-1-yl)ethoxy,    3-(1,2,4-triazol-1-yl)propoxy, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy,    pyrid-4-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3-ylethoxy,    2-pyrid-4-ylethoxy, 3-pyrid-2-ylpropoxy, 3-pyrid-3-ylpropoxy,    3-pyrid-4-ylpropoxy, 2-pyrrolidin-1-ylethoxy,    3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy,    pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,    3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,    4-morpholinobutoxy,    2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy, 3-(1,    1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,    3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy,    piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy,    2-piperidin-3-ylethoxy, 3-piperidin-3-ylpropoxy,    2-piperidin-4-ylethoxy, 3-piperidin-4-ylpropoxy,    2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy,    2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy,    4-piperazin-1-ylbutoxy, 2-homopiperazin-1-ylethoxy,    3-homopiperazin-1-ylpropoxy, 2-pyrrolidin-1-ylethylamino,    3-pyrrolidin-1-ylpropylamino, 4-pyrrolidin-1-ylbutylamino,    pyrrolidin-3-ylamino, pyrrolidin-2-ylmethylamino,    2-pyrrolidin-2-ylethylamino, 3-pyrrolidin-2-ylpropylamino,    2-morpholinoethylamino, 3-morpholinopropylamino,    4-morpholinobutylamino,    2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethylamino,    3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propylamino,    2-piperidinoethylamino, 3-piperidinopropylamino,    4-piperidinobutylamino, piperidin-3-ylamino, piperidin-4-ylamino,    piperidin-3-ylmethylamino, 2-piperidin-3-ylethylamino,    piperidin-4-ylmethylamino, 2-piperidin-4-ylethylamino,    2-homopiperidin-1-ylethylamino, 3-homopiperidin-1-ylpropylamino,    2-piperazin-1-ylethylamino, 3-piperazin-1-ylpropylamino,    4-piperazin-1-ylbutylamino, 2-homopiperazin-1-ylethylamino or    3-homopiperazin-1-ylpropylamino,

and wherein adjacent carbon atoms in any (2–6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, NH, N(Me), CH═CH and C≡C,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more fluoro or chloro groupsor a substituent selected from hydroxy, amino, methoxy, methylsulphonyl,methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino,N-isopropyl-N-methylamino, N-methyl-N-propylamino, acetoxy, acetamidoand N-methylacetamido,

and wherein any phenyl, imidazolyl, triazolyl, pyridyl or heterocyclylgroup within a substituent on R¹ optionally bears 1 or 2 substituents,which may be the same or different, selected from fluoro, chloro,trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl,N-methylcarbamoyl, N,N-dimethylcarbamoyl and methoxy, and apyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl orhomopiperazin-1-yl group within a R¹ substituent is optionallyN-substituted with allyl, 2-propynyl, methylsulphonyl, acetyl,2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-aminoethyl,3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl,2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-pyrrolidin-1-ylethyl,3-pyrrolidin-1-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl,2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-1-ylethyl or3-piperazin-1-ylpropyl, the last 8 of which substituents each optionallybears 1 or 2 substituents, which may be the same or different, selectedfrom fluoro, chloro, methyl and methoxy,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1 or 2 oxo substituents;

-   (l) n is 0;-   (m) n is 1 or 2 and the R³ groups, which may be the same or    different, are located at the 5- and/or 6-positions of the    1,3-benzodioxol-4-yl group and are selected from halogeno,    trifluoromethyl cyano, hydroxy, (1–6C)alkyl, (2–8C)alkenyl,    (2–8C)alkynyl, (1–6C)alkoxy, (1–6C)alkylthio, (1–6C)alkylsulphinyl,    (1–6C)alkylsulphonyl or from a group of the formula:    —X⁶—R¹¹    wherein X⁶ is a direct bond and R¹¹ is hydroxy-(1–6C)alkyl,    (1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl, amino-(1–6C)alkyl,    (1–6C)alkylamino-(1–6C)alkyl or di-[(1–6C)alkyl]amino-(1–6C)alkyl;-   (n) n is 1 or 2 and the R³ groups, which may be the same or    different, are located at the 5- and/or 6-positions of the    1,3-benzodioxol-4-yl group and are selected from halogeno,    trifluoromethyl, cyano, hydroxy, (1–6C)alkyl, (2–8C)alkenyl,    (2–8C)alkynyl and (1–6C)alkoxy;-   (o) n is 1 or 2 and the R³ groups, which may be the same or    different, are located at the 5- and/or 6-positions of the    1,3-benzodioxol-4-yl group and are selected from fluoro, chloro,    bromo, iodo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl,    allyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl, methoxy and    ethoxy;-   (p) n is 1 and the R³ group is located at the 5- or 6-position of    the 1,3-benzodioxol-4-yl group, especially the 5-position, and is    selected from chloro, bromo, trifluoromethyl, cyano, hydroxy,    methyl, ethyl, methoxy and ethoxy;-   (q) n is 1 and the R³ group is located at the 5- or 6-position of    the 1,3-benzodioxol-4-yl group, especially the 5-position, and is    selected from fluoro, chloro, bromo, trifluoromethyl, cyano,    hydroxy, methyl, ethyl, methoxy and ethoxy;-   (r) the -Z²-R¹⁴ group is located at the 7- or 6-position on the    1,3-benzodioxol-4-yl group;-   (s) the -Z²-R¹⁴ group is located at the 7-position on the    1,3-benzodioxol-4-yl group;-   (t) Z² is a C≡C group;-   (u) Z² is a CH═CH group;-   (v) R¹⁴ is selected from halogeno, cyano, formyl, carboxy,    carbamoyl, (2–8C)alkenyl, (1–6C)alkoxycarbonyl,    N-(1–6C)alkylcarbamoyl, N,N-di-[(1–6C)alkyl]carbamoyl,-   (2–6C)alkanoyl, N-(1–6C)alkylsulphamoyl,    N,N-di-[(1–6C)alkyl]sulphamoyl, halogeno-(1–6C)alkyl,    hydroxy-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl,    amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl,    di-[(1–6C)alkyl]amino-(1–6C)alkyl, (2–6C)alkanoylamino-(1–6C)alkyl    or from a group of the formula:    —X⁷-Q⁵    wherein X⁷ is a direct bond or CO and Q⁵ is aryl, aryl-(1–6C)alkyl,    heteroaryl, heteroaryl-(1–6C)alkyl, heterocyclyl or    heterocyclyl-(1–6C)alkyl,

and wherein any CH₂ or CH₃ group within a R¹⁴ substituent optionallybears on each said CH₂ or CH₃ group one or more halogeno or (1–6C)alkylsubstituents or a substituent selected from hydroxy, cyano, amino,(1–6C)alkoxy, (1–6C)alkylthio, (1–6C)alkylsulphinyl,(1–6C)alkylsulphonyl, (1–6C)alkylamino, di-[(1–6C)alkyl]amino,(2–6C)alkanoyl, (2–6C)alkanoyloxy, (2–6C)alkanoylamino,N-(1–6C)alkyl-(2–6C)alkanoylamino or from a group of the formula:—X⁸-Q⁶wherein X⁸ is a direct bond or is selected from O, N(R¹⁶), CON(R¹⁶),N(R¹⁶)CO and C(R¹⁶)₂O, wherein R¹⁶ is hydrogen or (1–6C)alkyl, and Q⁶ isheteroaryl, heteroaryl-(1–6C)alkyl, heterocyclyl orheterocyclyl-(1–6C)alkyl,

and wherein any aryl, heteroaryl or heterocyclyl group within asubstituent on R¹⁵ optionally bears 1, 2 or 3 substituents, which may bethe same or different, selected from halogeno, trifluoromethyl, hydroxy,amino, carbamoyl, (1–6C)alkyl, (2–8C)alkenyl, (2–8C)alkynyl,(1–6C)alkoxy, (1–6C)alkylsulphonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl and (2–6C)alkanoyl, or optionally bears 1substituent selected from a group of the formula:—X⁹—R¹⁷wherein X⁹ is a direct bond or is selected from O and N(R¹⁸), whereinR¹⁸ is hydrogen or (1–6C)alkyl, and R¹⁷ is hydroxy-(1–6C)alkyl,(1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl, amino-(1–6C)alkyl,(1–6C)alkylamino-(1–6C)alkyl, di-[(1–6C)alkyl]amino-(1–6C)alkyl,(2–6C)alkanoylamino-(1–6C)alkyl, (1–6C)alkoxycarbonylamino-(1–6C)alkyl,and from a group of the formula:—X¹⁰-Q⁷wherein X¹⁰ is a direct bond or is selected from O, N(R¹⁹) and CO,wherein R¹⁹ is hydrogen or (1–6C)alkyl, and Q⁷ is heterocyclyl orheterocyclyl-(1–6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1–6C)alkyland (1–6C)alkoxy,

and wherein any heterocyclyl group within a substituent on R¹⁴optionally bears 1 or 2 oxo substituents;

-   (w) R¹⁴ is selected from chloro, cyano, formyl, carboxy, carbamoyl,    methoxycarbonyl, vinyl, ethoxycarbonyl, N-methylcarbamoyl,    N-ethylcarbamoyl, N N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl,    N,N-diethylcarbamoyl, acetyl, propionyl, chloromethyl,    2-chloroethyl, 3-chloropropyl, hydroxymethyl, 2-hydroxyethyl,    3-hydroxypropyl, methoxymethyl, 2-methoxyethyl, 3-methoxypropyl,    cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, aminomethyl, 2-aminoethyl,    3-aminopropyl, methylaminomethyl ethylaminomethyl,    2-methylaminoethyl, 3-methylaminopropyl, 2-ethylaminoethyl,    3-ethylaminopropyl, dimethylaminomethyl, 2-dimethylaminoethyl,    3-dimethylaminopropyl, acetamidomethyl, 2-acetamidoethyl,    3-acetamidopropyl or from a group of the formula:    —X⁷-Q⁵    wherein-X⁷ is a direct bond or CO and Q⁵ is phenyl, benzyl, 1-, 2-    or 3-pyrrolidinyl, morpholino,    1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, piperidino, piperidin-3-yl,    piperidin-4-yl, 1-, 3- or 4-homopiperidinyl, piperazin-1-yl,    homopiperazin-1-yl, 1-, 2- or 3-pyrrolidinylmethyl,    morpholinomethyl, piperidinomethyl, 3- or 4-piperidinylmethyl, 1-,    3- or 4-homopiperidinylmethyl,    1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl, piperazin-1-ylmethyl,    homopiperazin-1-ylmethyl, 2-pyrrolidin-1-ylethyl,    3-pyrrolidin-1-ylpropyl, 2-pyrrolidin-2-ylethyl,    3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl,    2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethyl,    3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propyl,    2-piperidinoethyl, 3-piperidinopropyl, 2-piperidin-3-ylethyl,    3-piperidin-3-ylpropyl, 2-piperidin-4-ylethyl,    3-piperidin-4-ylpropyl, 2-homopiperidin-1-ylethyl,    3-homopiperidin-1-ylpropyl, 2-piperazin-1-ylethyl,    3-piperazin-1-ylpropyl, 2-homopiperazin-1-ylethyl or    3-homopiperazin-1-ylpropyl,

and wherein any CH₂ or CH₃ group within a R¹⁴ substituent optionallybears on each said CH₂ or CH₃ group one or more fluoro, chloro or methylgroups or a substituent selected from hydroxy, amino, methoxy,methylsulphonyl, methylamino, dimethylamino, diisopropylamino,N-ethyl-N-methylamino, N-isopropyl-N-methylamino,N-methyl-N-propylamino, acetoxy, acetamido and N-methylacetamido, orfrom a group of the formula:—X⁸-Q⁶wherein X⁸ is a direct bond or is selected from O, NH, CONH, NHCO andCH₂O and Q⁶ is pyridyl, pyridylmethyl, pyrrolidin-1-yl, pyrrolidin-2-yl,morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl,2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, pyrrolidin-2-ylmethyl,2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl,3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl,2-piperidin-4-ylethyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl,

and wherein any aryl, heteroaryl or heterocyclyl group within asubstituent on R¹⁴ optionally bears 1, 2 or 3 substituents, which may bethe same or different, selected from fluoro, chloro, trifluoromethyl,hydroxy, amino, carbamoyl, methyl, ethyl, allyl, 2-propynyl, methoxy,methylsulphonyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl and acetyl, oroptionally bears 1 substituent selected from a group of the formula:—X⁹—R¹⁷wherein X⁹ is a direct bond or is selected from O and NH and R¹⁷ is2-fluoroethyl, 3-fluoropropyl, 2-hydroxyethyl, 3-hydroxypropyl,2-methoxyethyl, 3-methoxypropyl, cyanomethyl, aminomethyl, 2-aminoethyl,3-aminopropyl, methylaminomethyl, 2-methylaminoethyl,3-methylaminopropyl, 2-ethylaminoethyl, 3-ethylaminopropyl,dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl,acetamidomethyl, methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl,tert-butoxycarbonylaminomethyl and from a group of the formula:—X¹⁰-Q⁷wherein X¹⁰ is a direct bond or is selected from O, NH and CO and Q⁷ ispyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl,morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl,piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl,piperazin-1-ylmethyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl,each of which optionally bears 1 or 2 substituents, which may be thesame or different, selected from fluoro, chloro, methyl and methoxy,

and wherein any heterocyclyl group within a substituent on R¹⁴optionally bears 1 or 2 oxo substituents; and

-   (x) R¹⁴ is selected from chloro, cyano, formyl, carboxy, carbamoyl,    vinyl, methoxycarbonyl, ethoxycarbonyl, N-methylcarbamoyl,    N-ethylcarbamoyl, N N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl,    N,N-diethylcarbamoyl, acetyl, propionyl, chloromethyl,    2-chloroethyl, 3-chloropropyl, hydroxymethyl, 2-hydroxyethyl,    3-hydroxypropyl, methoxymethyl, 2-methoxyethyl, 3-methoxypropyl,    cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, aminomethyl, 2-aminoethyl,    3-aminopropyl, methylaminomethyl, ethylaminomethyl,    2-methylaminoethyl, 3-methylaminopropyl, 2-ethylaminoethyl,    3-ethylaminopropyl, dimethylaminomethyl, 2-dimethylaminoethyl,    3-dimethylaminopropyl, acetamidomethyl, 2-acetamidoethyl,    3-acetamidopropyl or from a group of the formula:    —X⁷-Q⁵    wherein X⁷ is a direct bond or CO and Q⁵ is phenyl, benzyl, 1-, 2-    or 3-pyrrolidinyl, morpholino,    1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, pyridin-2-yl, piperidino,    piperidin-3-yl, piperidin-4-yl, 1-, 3- or 4-homopiperidinyl,    piperazin-1-yl, homopiperazin-1-yl, 1-, 2- or 3-pyrrolidinylmethyl,    morpholinomethyl, piperidinomethyl, 3- or 4-piperidinylmethyl, 1-,    3- or 4-homopiperidinylmethyl,    1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl, piperazin-1-ylmethyl,    homopiperazin-1-ylmethyl, 2-pyrrolidin-1-ylethyl,    3-pyrrolidin-1-ylpropyl, 2-pyrrolidin-2-ylethyl,    3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl,    2-(1,1-dioxotetrahydro-4H-1,4′ thiazin-4-yl)ethyl,    3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propyl,    2-piperidinoethyl, 3-piperidinopropyl, 2-piperidin-3-ylethyl,    3-piperidin-3-ylpropyl, 2-piperidin-4-ylethyl,    3-piperidin-4-ylpropyl, 2-homopiperidin-1-ylethyl,    3-homopiperidin-1-ylpropyl, 2-piperazin-1-ylethyl,    3-piperazin-1-ylpropyl, 2-homopiperazin-1-ylethyl or    3-homopiperazin-1-ylpropyl,

and wherein any CH₂ or CH₃ group within a R¹⁴ substituent optionallybears on each said CH₂ or CH₃ group one or more fluoro, chloro or methylgroups or a substituent selected from hydroxy, amino, methoxy,methylsulphonyl, methylamino, dimethylamino, diisopropylamino,N-ethyl-N-methylamino, N-isopropyl-N-methylamino,N-methyl-N-propylamino, acetoxy, acetamido and N-methylacetamido, orfrom a group of the formula:—X⁸-Q⁶wherein X⁸ is a direct bond or is selected from O, NH, CONH, NHCO andCH₂O and Q⁶ is pyridyl, pyridylmethyl, pyrrolidin-1-yl, pyrrolidin-2-yl,morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl,2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, pyrrolidin-2-ylmethyl,2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl,3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl,2-piperidin-4-ylethyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl,

and wherein any aryl, heteroaryl or heterocyclyl group within asubstituent on R¹⁴ optionally bears 1, 2 or 3 substituents, which may bethe same or different, selected from fluoro, chloro, trifluoromethyl,hydroxy, amino, carbamoyl, methyl, ethyl, allyl, 2-propynyl, methoxy,methylsulphonyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl and acetyl, oroptionally bears 1 substituent selected from a group of the formula:—X⁹—R¹⁷wherein X⁹ is a direct bond or is selected from O and NH and R¹⁷ is2-fluoroethyl, 3-fluoropropyl, 2-hydroxyethyl, 3-hydroxypropyl,2-methoxyethyl, 3-methoxypropyl, cyanomethyl, aminomethyl, 2-aminoethyl,3-aminopropyl, methylaminomethyl, 2-methylaminoethyl,3-methylaminopropyl, 2-ethylaminoethyl, 3-ethylaminopropyl,dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl,acetamidomethyl, methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl,tert-butoxycarbonylaminomethyl and from a group of the formula:—X¹⁰-Q⁷wherein X¹⁰ is a direct bond or is selected from O, NH and CO and Q⁷ ispyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl,morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl,piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl,piperazin-1-ylmethyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl,each of which optionally bears 1 or 2 substituents, which may be thesame or different, selected from fluoro, chloro, methyl and methoxy,

and wherein any heterocyclyl group within a substituent on R¹⁴optionally bears 1 or 2 oxo substituents; and

-   (y) R¹⁴ is selected from cyano, formyl, carboxy, carbamoyl, vinyl,    methoxycarbonyl, ethoxycarbonyl, N-methylcarbamoyl,    N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl,    N,N-diethylcarbamoyl, acetyl, propionyl, chloromethyl,    2-chloroethyl, 3-chloropropyl, hydroxymethyl, 2-hydroxyethyl,    3-hydroxypropyl, methoxymethyl, 2-methoxyethyl, 3-methoxypropyl or    from a group of the formula:    —X⁷-Q⁵    wherein X⁷ is a direct bond or CO and Q⁵ is pyridin-2-yl,    1-pyrrolidinyl, morpholino, 1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl,    piperidino, 1-homopiperidinyl, piperazin-1-yl,    homopiperazin-1-yl,1-pyrrolidinylmethyl, morpholinomethyl,    piperidinomethyl, 1-homopiperidinylmethyl,    1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl, piperazin-1-ylmethyl,    homopiperazin-1-ylmethyl or 3-morpholinopropyl,

and wherein any CH₂ or CH₃ group within a R¹⁴ substituent optionallybears on each said CH₂ or CH₃ group one or more fluoro, chloro or methylgroups or a substituent selected from hydroxy, amino, methoxy,methylamino, dimethylamino, acetoxy, acetamido and N-methylacetamido,

and wherein any heteroaryl or heterocyclyl group within a substituent onR¹⁴ optionally bears 1, 2 or 3 substituents, which may be the same ordifferent, selected from hydroxy, amino, carbamoyl, methyl, ethyl,allyl, 2-propynyl, methoxy, methylsulphonyl, N-methylcarbamoyl,

-   N,N-dimethylcarbamoyl and acetyl, or optionally bears 1 substituent    selected from a group of the formula:    —X⁹—R¹⁷    wherein X⁹ is a direct bond and R¹⁷ is 2-fluoroethyl,    2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl,    cyanomethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl,    acetamidomethyl, methoxycarbonylaminomethyl,    ethoxycarbonylaminomethyl or tert-butoxycarbonylaminomethyl,

and wherein any heterocyclyl group within a substituent on R¹⁴optionally bears 1 or 2 oxo substituents.

A particular compound of the invention is a quinoline derivative of theFormula I wherein:

Z¹ is O or NH;

m is 1 and the R¹ group is located at the 5-, 6- or 7-position or m is 2and each R¹ group, which may be the same or different, is located at the5- and 7-positions or at the 6- and 7-positions and R¹ is selected fromhydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,isopropoxy, butoxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino,ethylamino, dimethylamino, diethylamino, acetamido, propionamido,2-imidazol-1-ylethoxy, 2-(1,2,4-triazol-1-yl)ethoxy,tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy,4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 4-morpholinobutoxy,2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy,piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy,2-piperidin-3-ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy,3-piperidin-4-ylpropoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy,2-homopiperazin-1-ylethoxy and 3-homopiperazin-1-ylpropoxy,

and wherein adjacent carbon atoms in any (2–6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, NH, N(Me), CH═CH and C≡C,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more fluoro or chloro groupsor a substituent selected from hydroxy, amino, methoxy, methylsulphonyl,methylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino,N-isopropyl-N-methylamino, N-methyl-N-propylamino and acetoxy;

and wherein any heteroaryl or heterocyclyl group within a substituent onR¹ optionally bears 1 or 2 substituents, which may be the same ordifferent, selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, carbamoyl, methyl, ethyl, methoxy, N-methylcarbamoyl andN,N-dimethylcarbamoyl and a pyrrolidin-2-yl, piperidin-3-yl,piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within a R¹substituent is optionally N-substituted with allyl, methylsulphonyl,acetyl, 2-fluoroethyl, 3-fluoropropyl, 2-methoxyethyl, 3-methoxypropyl,cyanomethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl,3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl,2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 2-morpholinoethyl,3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, the last 8 of whichsubstituents each optionally bears 1 or 2 substituents, which may be thesame or different, selected from fluoro, chloro, methyl and methoxy,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1 or 2 oxo substituents;

n is 0 or 1 and the R³ group, if present, is located at the 5- or6-position of the 1,3-benzodioxol-4-yl group and is selected fromfluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl,vinyl, allyl, ethynyl, methoxy and ethoxy;

Z² is a C≡C or CH═CH group; and

R¹⁴ is selected from cyano, formyl, carboxy, carbamoyl, methoxycarbonyl,ethoxycarbonyl, N-methylcarbamoyl, N-ethylcarbamoyl,N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl,acetyl, propionyl, chloromethyl, 2-chloroethyl, 3-chloropropyl,hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl,2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-cyanoethyl,3-cyanopropyl, methylaminomethyl, ethylaminomethyl, 2-methylaminoethyl,3-methylaminopropyl, 2-ethylaminoethyl, 3-ethylaminopropyl,dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl,acetamidomethyl, 2-acetamidoethyl and 3-acetamidopropyl, or from a groupof the formula:—X⁷-Q⁵wherein X⁷ is a direct bond or CO and Q⁵ is 1-pyrrolidinyl, morpholino,1,1-dioxotetrahydro-4H-1,4-thiazinyl, piperidino, 1-homopiperidinyl,piperazin-1-yl, homopiperazin-1-yl, 1-pyrrolidinylmethyl,morpholinomethyl, piperidinomethyl, 1-homopiperidinylmethyl,1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl, piperazin-1-ylmethyl,homopiperazin-1-ylmethyl or 3-morpholinopropyl,

and wherein any CH₂ or CH₃ group within a R¹⁴ substituent optionallybears on each said CH₂ or CH₃ group one or more fluoro, chloro or methylgroups or a substituent selected from hydroxy, amino, methoxy,methylamino, dimethylamino, acetoxy, acetamido and N-methylacetamido,

and wherein any heterocyclyl group within a substituent on R¹⁴optionally bears 1, 2 or 3 substituents, which may be the same ordifferent, selected from hydroxy, amino, carbamoyl, methyl, ethyl,allyl, 2-propynyl, methoxy, methylsulphonyl, N-methylcarbamoyl,N,N-dimethylcarbamoyl and acetyl, or optionally bears 1 substituentselected from a group of the formula:—X⁹—R¹⁷wherein X⁹ is a direct bond and R¹⁷ is 2-hydroxyethyl, 3-hydroxypropyl,2-methoxyethyl, 3-methoxypropyl, cyanomethyl, aminomethyl,methylaminomethyl, dimethylaminomethyl, acetamidomethyl,methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl ortert-butoxycarbonylaminomethyl,

and wherein any heterocyclyl group within a substituent on R¹⁴optionally bears 1 or 2 oxo substituents;

or a pharmaceutically-acceptable acid-addition salt thereof.

A particular compound of the invention is a quinoline derivative of theFormula I wherein:

Z¹ is O or NH,

m is 1 and the R¹ group is located at the 5-, 6- or 7-position or m is 2and each R¹ group, which may be the same or different, is located at the5- and 7-positions or at the 6- and 7-positions and R¹ is selected fromhydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,isopropoxy, butoxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino,ethylamino, dimethylamino, diethylamino, acetamido, propionamido,2-imidazol-1-ylethoxy, 2-(1,2,4-triazol-1-yl)ethoxy,tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy,4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 4-morpholinobutoxy,2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy,piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy,2-piperidin-3-ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy,3-piperidin-4-ylpropoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy,2-homopiperazin-1-ylethoxy and 3-homopiperazin-1-ylpropoxy,

and wherein adjacent carbon atoms in any (2–6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, NH, N(Me), CH═CH and C≡C,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more fluoro or chloro groupsor a substituent selected from hydroxy, amino, methoxy, methylsulphonyl,methylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino,N-isopropyl-N-methylamino, N-methyl-N-propylamino and acetoxy,

and wherein any heteroaryl or heterocyclyl group within a substituent onR¹ optionally bears 1 or 2 substituents, which may be the same ordifferent, selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, carbamoyl, methyl, ethyl, methoxy, N-methylcarbamoyl andN,N-dimethylcarbamoyl and a pyrrolidin-2-yl, piperidin-3-yl,piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within a R¹substituent is optionally N-substituted with allyl, methylsulphonyl,acetyl, 2-fluoroethyl, 3-fluoropropyl, 2-methoxyethyl, 3-methoxypropyl,cyanomethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl,3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl,2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 2-morpholinoethyl,3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, the last 8 of whichsubstituents each optionally bears 1 or 2 substituents, which may be thesame or different, selected from fluoro, chloro, methyl and methoxy,

and wherein any heterocyclyl group within a substituent on R¹ optionallybears 1 or 2 oxo substituents;

n is 0 or 1 and the R³ group, if present, is located at the 5- or6-position of the 1,3-benzodioxol-4-yl group and is selected fromfluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl,vinyl, allyl, ethynyl, methoxy and ethoxy;

Z² is a C≡C or CH═CH group; and

R¹⁴ is selected from cyano, formyl, carboxy, carbamoyl, vinyl,methoxycarbonyl, ethoxycarbonyl, N-methylcarbamoyl, N-ethylcarbamoyl, NN-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl,acetyl, propionyl, chloromethyl, 2-chloroethyl, 3-chloropropyl,hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl,2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-cyanoethyl,3-cyanopropyl, methylaminomethyl, ethylaminomethyl, 2-methylaminoethyl,3-methylaminopropyl, 2-ethylaminoethyl, 3-ethylaminopropyl,dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl,acetamidomethyl, 2-acetamidoethyl and 3-acetamidopropyl, or from a groupof the formula:—X⁷-Q⁵wherein X⁷ is a direct bond or CO and Q⁵ is pyridin-2-yl,1-pyrrolidinyl, morpholino, 1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl,piperidino, 1-homopiperidinyl, piperazin-1-yl, homopiperazin-1-yl,1-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl,1-homopiperidinylmethyl, 1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl,piperazin-1-ylmethyl, homopiperazin-1-ylmethyl or 3-morpholinopropyl,

and wherein any CH₂ or CH₃ group within a R¹⁴ substituent optionallybears on each said CH₂ or CH₃ group one or more fluoro, chloro or methylgroups or a substituent selected from hydroxy, amino, methoxy,methylamino, dimethylamino, acetoxy, acetamido and N-methylacetamido,

and wherein any heteroaryl or heterocyclyl group within a substituent onR¹⁴ optionally bears 1, 2 or 3 substituents, which may be the same ordifferent, selected from hydroxy, amino, carbamoyl, methyl, ethyl,allyl, 2-propynyl, methoxy, methylsulphonyl, N-methylcarbamoyl,

-   N,N-dimethylcarbamoyl and acetyl, or optionally bears 1 substituent    selected from a group of the formula:    —X⁹—R¹⁷    wherein X⁹ is a direct bond and R¹⁷ is 2-hydroxyethyl,    3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl,    aminomethyl, methylaminomethyl, dimethylaminomethyl,    acetamidomethyl, methoxycarbonylaminomethyl,    ethoxycarbonylaminomethyl or tert-butoxycarbonylaminomethyl,

and wherein any heterocyclyl group within a substituent on R¹⁴optionally bears 1 or 2 oxo substituents;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivativeof the Formula I wherein:

Z¹ is NH;

m is 2 and the first R¹ group is a 6-methoxy group and the second R¹group is located at the 7-position and is selected from methoxy, ethoxy,2-fluoroethoxy, 2-chloroethoxy, 3-fluoropropoxy, 3-chloropropoxy,2-methylsulphonylethoxy, 3-methylsulphonylpropoxy,2-(2-chloroethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-ylmethoxy,N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy,2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy,3-(N-methylpiperidin-3-yl)propoxy, 2-piperidin-4-ylethoxy,2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy,3-(N-methylpiperidin-4-yl)propoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 3-(4-allylpiperazin-1-yl)propoxy,3-(4-methylsulphonylpiperazin-1-yl)propoxy,3-(4-acetylpiperazin-1-yl)propoxy,2-(4-cyanomethylpiperazin-1-yl)ethoxy,3-(4-cyanomethylpiperazin-1-yl)propoxy,2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy,3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy,2-(3-oxopiperazin-1-yl)ethoxy, 3-(3-oxopiperazin-1-yl)propoxy,2-(2-pyrrolidin-1-ylethoxy)ethoxy, 2-(2-morpholinoethoxy)ethoxy,2-(2-piperidinoethoxy)ethoxy, 2-[2-(4-methylpiperazin-1-yl)ethoxy]ethoxyand 2-fluoro-3-(4-hydroxypiperidin-1-yl)propoxy;

n is 0 or n is 1 and the R³ group, if present, is located at the5-position of the 1,3-benzodioxol-4-yl group and is selected fromfluoro, chloro and bromo;

the -Z²-R¹⁴ group is located at the 7-position on the1,3-benzodioxol-4-yl group,

Z² is a C≡C or CH═CH group; and

R¹⁴ is selected from cyano, formyl, carboxy, carbamoyl, methoxycarbonyl,vinyl, ethoxycarbonyl, N-methylcarbamoyl, N-ethylcarbamoyl,N-(2-methoxyethyl)carbamoyl, N,N-dimethylcarbamoyl,N-ethyl-N-methylcarbamoyl, N-(2-methoxyethyl)-N-methylcarbamoyl, acetyl,propionyl, chloromethyl, 2-chloroethyl, 3-chloropropyl, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl, 2-methoxyethyl,3-methoxypropyl, dimethylaminomethyl, 2-dimethylaminoethyl,3-dimethylaminopropyl, pyridin-2-yl, 1-pyrrolidinylcarbonyl,morpholinocarbonyl, 1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylcarbonyl,piperidinocarbonyl, piperazin-1-ylcarbonyl, 1-pyrrolidinylmethyl,morpholinomethyl, piperidinomethyl,1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl, piperazin-1-ylmethyl and3-morpholinopropyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivativeof the Formula I wherein:

Z¹ is NH;

m is 2 and the first R¹ group is a 6-methoxy group and the second R¹group is located at the 7-position and is selected from methoxy, ethoxy,2-fluoroethoxy, 2-chloroethoxy, 3-fluoropropoxy, 3-chloropropoxy,2-methylsulphonylethoxy, 3-methylsulphonylpropoxy,2-(2-chloroethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-ylmethoxy,N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy,2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy,3-(N-methylpiperidin-3-yl)propoxy, 2-piperidin-4-ylethoxy,2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy,3-(N-methylpiperidin-4-yl)propoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 3-(4-allylpiperazin-1-yl)propoxy,3-(4-methylsulphonylpiperazin-1-yl)propoxy,3-(4-acetylpiperazin-1-yl)propoxy,2-(4-cyanomethylpiperazin-1-yl)ethoxy,3-(4-cyanomethylpiperazin-1-yl)propoxy,2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy,3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy,2-(3-oxopiperazin-1-yl)ethoxy, 3-(3-oxopiperazin-1-yl)propoxy,2-(2-pyrrolidin-1-ylethoxy)ethoxy, 2-(2-morpholinoethoxy)ethoxy,2-(2-piperidinoethoxy)ethoxy and2-[2-(4-methylpiperazin-1-yl)ethoxy]ethoxy;

n is 0 or n is 1 and the R³ group, if present, is located at the5-position of the 1,3-benzodioxol-4-yl group and is selected from chloroand bromo;

the -Z²-R¹⁴ group is located at the 7-position on the1,3-benzodioxol-4-yl group,

Z² is a C≡C or CH═CH group; and

-   -   R¹⁴ is selected from cyano, formyl, carboxy, carbamoyl,        methoxycarbonyl, ethoxycarbonyl, N-methylcarbamoyl,        N-ethylcarbamoyl, N-(2-methoxyethyl)carbamoyl,        N,N-methylcarbamoyl, N-ethyl-N-methylcarbamoyl,        N-(2-methoxyethyl)-N-methylcarbamoyl, acetyl, propionyl,        chloromethyl, 2-chloroethyl, 3-chloropropyl, hydroxymethyl,        2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl, 2-methoxyethyl,        3-methoxypropyl, dimethylaminomethyl, 2-dimethylaminoethyl,        3-dimethylaminopropyl, 1-pyrrolidinylcarbonyl,        morpholinocarbonyl,        1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylcarbonyl,        piperidinocarbonyl, piperazin-1-ylcarbonyl,        1-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl,        1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl,        piperazin-1-ylmethyl and 3-morpholinopropyl;        or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivativeof the Formula I wherein:

Z¹ is NH;

m is 2 and the first R¹ group is a 6-methoxy group and the second R¹group is located at the 7-position and is selected from methoxy, ethoxy,2-fluoroethoxy, 2-chloroethoxy, 3-fluoropropoxy, 3-chloropropoxy,2-methylsulphonylethoxy, 3-methylsulphonylpropoxy,2-(2-chloroethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-ylmethoxy,N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy,2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy,3-(N-methylpiperidin-3-yl)propoxy, 2-piperidin-4-ylethoxy,2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy,3-(N-methylpiperidin-4-yl)propoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 3-(4-allylpiperazin-1-yl)propoxy,3-(4-methylsulphonylpiperazin-1-yl)propoxy,3-(4-acetylpiperazin-1-yl)propoxy,2-(4-cyanomethylpiperazin-1-yl)ethoxy,3-(4-cyanomethylpiperazin-1-yl)propoxy,2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy,3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy,2-(3-oxopiperazin-1-yl)ethoxy, 3-(3-oxopiperazin-1-yl)propoxy,2-(2-pyrrolidin-1-ylethoxy)ethoxy, 2-(2-morpholinoethoxy)ethoxy,2-(2-piperidinoethoxy)ethoxy, 2-[2-(4-methylpiperazin-1-yl)ethoxy]ethoxyand 2-fluoro-3-(4-hydroxypiperidin-1-yl-propoxy;

n is 0 or n is 1 and the R³ group, if present, is located at the5-position of the 1,3-benziodioxol-4-yl group and is selected fromfluoro, chloro and bromo;

the -Z²-R¹⁴ group is located at the 7-position on the1,3-benzodioxol-4-yl group,

Z is a C≡C group; and

R¹⁴ is selected from chloromethyl, 2-chloroethyl, 3-chloropropyl,hydroxymethyl, vinyl

2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl, 2-methoxyethyl,3-methoxypropyl, dimethylaminomethyl, 2-dimethylaminoethyl,3-dimethylaminopropyl, pyridin-2-yl, 1-pyrrolidinylmethyl,morpholinomethyl, piperidinomethyl,1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl, piperazin-1-ylmethyl and3-morpholinopropyl;or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivativeof the Formula I wherein:

Z¹ is NH;

m is 2 and the first R¹ group is a 6-methoxy group and the second R¹group is located at the 7-position and is selected from methoxy, ethoxy,2-fluoroethoxy, 2-chloroethoxy, 3-fluoropropoxy, 3-chloropropoxy,2-methylsulphonylethoxy, 3-methylsulphonylpropoxy,2-(2-chloroethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-ylmethoxy,N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy,2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy,3-(N-methylpiperidin-3-yl)propoxy, 2-piperidin-4-ylethoxy,2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy,3-(N-methylpiperidin-4-yl)propoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 3-(4-allylpiperazin-1-yl)propoxy,3-(4-methylsulphonylpiperazin-1-yl)propoxy,3-(4-acetylpiperazin-1-yl)propoxy,2-(4-cyanomethylpiperazin-1-yl)ethoxy,3-(4-cyanomethylpiperazin-1-yl)propoxy,2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy,3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy,2-(3-oxopiperazin-1-yl)ethoxy, 3-(3-oxopiperazin-1-yl)propoxy,2-(2-pyrrolidin-1-ylethoxy)ethoxy, 2-(2-morpholinoethoxy)ethoxy,2-(2-piperidinoethoxy)ethoxy and2-[2-(4-methylpiperazin-1-yl)ethoxy]ethoxy;

n is 0 or n is 1 and the R³ group, if present, is located at the5-position of the 1,3-benzodioxol-4-yl group and is selected from chloroand bromo;

the -Z²-R¹⁴ group is located at the 7-position on the1,3-benzodioxol-4-yl group,

Z² is a CH═CH group; and

R¹⁴ is selected from cyano, formyl, carboxy, carbamoyl, methoxycarbonyl,ethoxycarbonyl, N-methylcarbamoyl, N-ethylcarbamoyl,N-(2-methoxyethyl)carbamoyl, N,N-dimethylcarbamoyl,N-ethyl-N-methylcarbamoyl, N-(2-methoxyethyl)-N-methylcarbamoyl, acetyl,propionyl, chloromethyl, 2-chloroethyl, 3-chloropropyl, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl, 2-methoxyethyl,3-methoxypropyl, dimethylaminomethyl, 2-dimethylaminoethyl,3-dimethylaminopropyl, 1-pyrrolidinylcarbonyl, morpholinocarbonyl,1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylcarbonyl, piperidinocarbonyl,piperazin-1-ylcarbonyl, 1-pyrrolidinyl-methyl, morpholinomethyl,piperidinomethyl, 1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl andpiperazin-1-ylmethyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivativeof the Formula I wherein:

Z¹ is NH;

m is 2 and the first R¹ group is a 6-methoxy group and the second R¹group is located at the 7-position and is selected from methoxy, ethoxy,2-fluoroethoxy, 2-chloroethoxy, 3-fluoropropoxy, 3-chloropropoxy,2-(2-chloroethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 3-(4-allylpiperazin-1-yl)propoxy,3-(4-methylsulphonylpiperazin-1-yl)propoxy,3-(4-acetylpiperazin-1-yl)propoxy,2-(4-cyanomethylpiperazin-1-yl)ethoxy,3-(4-cyanomethylpiperazin-1-yl)propoxy,2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy,3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy,2-(3-oxopiperazin-1-yl)ethoxy, 3-(3-oxopiperazin-1-yl)propoxy,2-(2-pyrrolidin-1-ylethoxy)ethoxy and2-fluoro-3-(4-hydroxypiperidin-1-yl)propoxy;

n is 0 or n is 1 and R³ is a fluoro or chloro group located at the5-position of the 1,3-benzodioxol-4-yl group;

the -Z²-R¹⁴ group is located at the 7-position on the1,3-benzodioxol-4-yl group,

Z² is a C≡C group; and

-   -   R¹⁴ is selected from vinyl, hydroxymethyl, methoxymethyl,        dimethylaminomethyl, pyridin-2-yl, 1-pyrrolidinylmethyl,        morpholinomethyl, piperidinomethyl,        1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl and        piperazin-1-ylmethyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivativeof the Formula I wherein:

Z¹ is NH

m is 2 and the first R¹ group is a 6-methoxy group and the second R¹group is located at the 7-position and is selected from methoxy, ethoxy,2-fluoroethoxy, 2-chloroethoxy, 3-fluoropropoxy, 3-chloropropoxy,2-(2-chloroethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 3-(4-allylpiperazin-1-yl)propoxy,3-(4-methylsulphonylpiperazin-1-yl)propoxy,3-(4-acetylpiperazin-1-yl)propoxy,2-(4-cyanomethylpiperazin-1-yl)ethoxy,3-(4-cyanomethylpiperazin-1-yl)propoxy,2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy,3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy,2-(3-oxopiperazin-1-yl)ethoxy, 3-(3-oxopiperazin-1-yl)propoxy and2-(2-pyrrolidin-1-ylethoxy)ethoxy;

n is 0 or n is 1 and R³ is a chloro group located at the 5-position ofthe 1,3-benzodioxol-4-yl group;

the -Z²-R¹⁴ group is located at the 7-position on the1,3-benzodioxol-4-yl group,

Z² is a C≡C group; and

R¹⁴ is selected from hydroxymethyl, methoxymethyl, dimethylaminomethyl,1-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl,1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl and piperazin-1-ylmethyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivativeof the Formula I wherein:

Z¹ is NH;

m is 2 and the first R¹ group is a 6-methoxy group and the second R¹group is located at the 7-position and is selected from methoxy, ethoxy,2-fluoroethoxy, 2-chloroethoxy, 3-fluoropropoxy, 3-chloropropoxy,2-(2-chloroethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 3-(4-allylpiperazin-1-yl)propoxy,3-(4-methylsulphonylpiperazin-1-yl)propoxy,3-(4-acetylpiperazin-1-yl)propoxy,2-(4-cyanomethylpiperazin-1-yl)ethoxy,3-(4-cyanomethylpiperazin-1-yl)propoxy,2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy,3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy,2-(3-oxopiperazin-1-yl)ethoxy, 3-(3-oxopiperazin-1-yl)propoxy and2-(2-pyrrolidin-1-ylethoxy)ethoxy;

n is 0 or n is 1 and R³ is a chloro group located at the 5-position ofthe 1,3-benziodioxol-4-yl group;

the -Z²-R⁴ group is located at the 7-position on the1,3-benzodioxol-4-yl group,

Z² is a CH═CH group; and

R¹⁴ is selected from cyano, carboxy, carbamoyl, methoxycarbonyl,ethoxycarbonyl, N-methylcarbamoyl, N-ethylcarbamoyl,N-(2-methoxyethyl)carbamoyl, N,N-dimethylcarbamoyl,N-ethyl-N-methylcarbamoyl, N-(2-methoxyethyl)-N-methylcarbamoyl, acetyl,propionyl, 1-pyrrolidinylcarbonyl, morpholinocarbonyl,1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylcarbonyl, piperidinocarbonyl andpiperazin-1-ylcarbonyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivativeof the Formula I wherein:

Z¹ is NH;

m is 2 and the first R¹ group is located at the 5-position and isselected from N-methylpiperidin-4-yloxy and tetrahydro-2H-pyran-4-yloxyand the second R¹ group is located at the 7-position and is selectedfrom methoxy, ethoxy, 2-fluoroethoxy, 2-chloroethoxy, 3-fluoropropoxy,3-chloropropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy,2-(2-chloroethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-ylmethoxy,N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy,2-(N-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy,3-(E-methylpiperidin-3-yl)propoxy, 2-piperidin-4-ylethoxy,2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy,3-(N-methylpiperidin-4-yl)propoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 3-(4-allylpiperazin-1-yl)propoxy,3-(4-methylsulphonylpiperazin-1-yl)propoxy,3-(4-acetylpiperazin-1-yl)propoxy,2-(4-cyanomethylpiperazin-1-yl)ethoxy,3-(4-cyanomethylpiperazin-1-yl)propoxy,2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy,3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy,2-(3-oxopiperazin-1-yl)ethoxy, 3-(3-oxopiperazin-1-yl)propoxy,2-(2-pyrrolidin-1-ylethoxy)ethoxy, 2-(2-morpholinoethoxy)ethoxy,2-(2-piperidinoethoxy)ethoxy, 2-[2-(4-methylpiperazin-1-yl)ethoxy]ethoxyand 2-fluoro-3-(4-hydroxypiperidin-1-yl)propoxy;

n is 0 or n is 1 and R³ is located at the 5-position of the1,3-benzodioxol-4-yl group and is selected from a fluoro, chloro orbromo group;

the -Z²-R¹⁴ group is located at the 7-position on the1,3-benzodioxol-4-yl group,

Z² is a C≡C group; and

R¹⁴ is selected from cyano, formyl, carboxy, carbamoyl, vinyl,methoxycarbonyl, ethoxycarbonyl, N-methylcarbamoyl, N-ethylcarbamoyl,N-(2-methoxyethyl)carbamoyl, N,N-dimethylcarbamoyl,N-ethyl-N-methylcarbamoyl, N-(2-methoxyethyl)-N-methylcarbamoyl, acetyl,propionyl, chloromethyl, 2-chloroethyl, 3-chloropropyl, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl, 2-methoxyethyl,3-methoxypropyl, dimethylaminomethyl, 2-dimethylaminoethyl,3-dimethylaminopropyl, 1-pyrrolidinylcarbonyl, morpholinocarbonyl,1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylcarbonyl, piperidinocarbonyl,piperazin-1-ylcarbonyl, 1-pyrrolidinylmethyl, morpholinomethyl,piperidinomethyl, 1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl,piperazin-1-ylmethyl and 3-morpholinopropyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivativeof the Formula I wherein:

Z¹ is NH;

m is 2 and the first R¹ group is located at the 5-position and isselected from N-methylpiperidin-4-yloxy and tetrahydro-2H-pyran-4-yloxyand the second R¹ group is located at the 7-position and is selectedfrom methoxy and 3-morpholinopropoxy,

n is 0 or n is 1 and R³ is located at the 5-position of the1,3-benzodioxol-4-yl group and is selected from a fluoro, chloro orbromo group;

the -Z²-R¹⁴ group is located at the 7-position on the1,3-benzodioxol-4-yl group,

Z² is a C≡C group; and

R¹⁴ is selected from chloromethyl, 2-chloroethyl, 3-chloropropyl,hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl,2-methoxyethyl, 3-methoxypropyl, dimethylaminomethyl,2-dimethylaminoethyl, 3-dimethylaminopropyl, pyridin-2-yl,1-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl,1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl, piperazin-1-ylmethyl and3-morpholinopropyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivativeof the Formula I wherein:

Z¹ is NH;

m is 2 and the first R¹ group is located at the 5-position and isselected from N-methylpiperidin-4-yloxy and tetrahydro-2H-pyran-4-yloxyand the second R¹ group is located at the 7-position and is selectedfrom methoxy and 3-morpholinopropoxy,

n is 0 or n is 1 and the R³ group, if present, is located at the5-position of the 1,3-benziodioxol-4-yl group and is chloro;

the -Z²-R¹⁴ group is located at the 7-position on the1,3-benzodioxol-4-yl group,

Z² is a C≡C group; and

R¹⁴ is selected from methoxymethyl and 2-methoxyethyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

Particular compounds of the invention include, for example, thequinoline derivatives of the Formula I described hereinafter in Examples1, 2, 3, 9(1) to 9(7), 10 and 11. Particular compounds also include3-cyano-4-[6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline,3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline,3-cyano-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline,3-cyano-7-methoxy-4-[4-(4-methoxybut-1-ynyl)-2,3-methylenedioxyanilino]-5-[(1-methylpiperidin-4-yl)oxy]quinoline,3-cyano-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]4[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline,3-cyano-6,7-dimethoxy-4-[4-(pyridin-2-ylethynyl)-2,3-methylenedioxyanilino]quinoline,3-cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]-7-[2-(2-pyrrolidin-1-ylethoxy)ethoxy]-quinoline,4-[(4-but-3-en-1-ynyl-2,3-methylendioxy)anilino]-3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline,3-cyano-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]-4-[6-fluoro-4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline,3-cyano-6-methoxy-7-[2-fluoro-3-(4-hydroxypiperidin-1-yl)propoxy]-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinolineand3-cyano-6-methoxy-7-[2-(2-methoxyethoxy)ethoxy]4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline.

A quinoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, may be prepared by any processknown to be applicable to the preparation of chemically-relatedcompounds. Such processes, when used to prepare a quinoline derivativeof the Formula I are provided as a further feature of the invention andare illustrated by the following representative process variants inwhich, unless otherwise stated, m, R¹, Z¹, n, R³, Z² and R¹⁴ have any ofthe meanings defined hereinbefore. Necessary starting materials may beobtained by standard procedures of organic chemistry. The preparation ofsuch starting materials is described in conjunction with the followingrepresentative process variants and within the accompanying Examples.Alternatively necessary starting materials are obtainable by analogousprocedures to those illustrated which are within the ordinary skill ofan organic chemist.

-   (a) For the production of those compounds of the Formula I wherein    Z¹ is an O, S or N(R²) group, the reaction of a quinoline of the    Formula II

wherein L is a displaceable group and m and R¹ have any of the meaningsdefined hereinbefore except that any functional group is protected ifnecessary, with a compound of the Formula III

wherein Z¹ is O, S, or N(R²) and n, R³, R², Z² and R¹⁴ have any of themeanings defined hereinbefore except that any functional group isprotected if necessary, whereafter any protecting group that is presentis removed by conventional means.

The reaction may conveniently be carried out in the presence of asuitable acid or in the presence of a suitable base. A suitable acid is,for example, an inorganic acid such as, for example, hydrogen chlorideor hydrogen bromide. A suitable base is, for example, an organic aminebase such as, for example, pyridine, 2,6-lutidine, collidine,4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholineor diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali oralkaline earth metal carbonate or hydroxide, for example sodiumcarbonate, potassium carbonate, calcium carbonate, sodium hydroxide orpotassium hydroxide, or, for example, an alkali metal amide, for examplesodium hexamethyldisilazane, or, for example, an alkali metal hydride,for example sodium hydride.

A suitable displaceable group L is, for example, a halogeno, alkoxy,aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy,phenoxy, pentafluorophenoxy, methanesulphonyloxy ortoluene-4-sulphonyloxy group. The reaction is conveniently carried outin the presence of a suitable inert solvent or diluent, for example analcohol or ester such as methanol, ethanol, isopropanol or ethylacetate, a halogenated solvent such as methylene chloride, chloroform orcarbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, anaromatic solvent such as toluene, or a dipolar aprotic solvent such asN,N-dimethylformamide, N,N-dimethylacetamide N-methylpyrrolidin-2-one ordimethylsulphoxide. The reaction is conveniently carried out at atemperature in the range, for example, 0 to 250° C., preferably in therange 0 to 120° C.

Typically, the quinoline of the Formula II may be reacted with acompound of the Formula III in the presence of an aprotic solvent suchas N,N-dimethylformamide, conveniently in the presence of a base, forexample potassium carbonate or sodium hexamethyldisilazane, and at atemperature in the range, for example, 0 to 150° C., preferably in therange, for example, 0 to 70° C.

The quinoline derivative of the Formula I may be obtained from thisprocess in the form of the free base or alternatively it may be obtainedin the form of a salt with the acid of the formula H-L wherein L has themeaning defined hereinbefore. When it is desired to obtain the free basefrom the salt, the salt may be treated with a suitable base, forexample, an organic amine base such as, for example, pyridine,2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or,for example, an alkali or alkaline earth metal carbonate or hydroxide,for example sodium carbonate, potassium carbonate, calcium carbonate,sodium hydroxide or potassium hydroxide.

Protecting groups may in general be chosen from any of the groupsdescribed in the literature or known to the skilled chemist asappropriate for the protection of the group in question and may beintroduced by conventional methods. Protecting groups may be removed byany convenient method as described in the literature or known to theskilled chemist as appropriate for the removal of the protecting groupin question, such methods being chosen so as to effect removal of theprotecting group with minimum disturbance of groups elsewhere in themolecule.

Specific examples of protecting groups are given below for the sake ofconvenience, in which “lower”, as in, for example, lower alkyl,signifies that the group to which it is applied preferably has 1–4carbon atoms. It will be understood that these examples are notexhaustive. Where specific examples of methods for the removal ofprotecting groups are given below these are similarly not exhaustive.The use of protecting groups and methods of deprotection notspecifically mentioned are, of course, within the scope of theinvention.

A carboxy protecting group may be the residue of an ester-formingaliphatic or arylaliphatic alcohol or of an ester-forming silanol (thesaid alcohol or silanol preferably containing 1–20 carbon atoms).Examples of carboxy protecting groups include straight or branched chain(1–12C)alkyl groups (for example isopropyl, and tert-butyl); loweralkoxy-lower alkyl groups (for example methoxymethyl, ethoxymethyl andisobutoxymethyl); lower acyloxy-lower alkyl groups, (for exampleacetoxymethyl, propionyloxymethyl, butyryloxymethyl andpivaloyloxymethyl); lower alkoxycarbonyloxy-lower allyl groups (forexample 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl);aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl,2-nitrobenzyl, 4-nitrobenzyl, benzhydryl and phthalidyl); tri(lowerallyl)silyl groups (for example trimethylsilyl andtert-butyldimethylsilyl); tri(lower alkyl)silyl-lower alkyl groups (forexample trimethylsilylethyl); and (2–6C)alkenyl groups (for exampleallyl). Methods particularly appropriate for the removal of carboxylprotecting groups include for example acid-, base-, metal- orenzymically-catalysed cleavage.

Examples of hydroxy protecting groups include lower alkyl groups (forexample tert-butyl), lower alkenyl groups (for example allyl); loweralkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (forexample tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (forexample allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for examplebenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyland 4-nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (for exampletrimethylsilyl and tert-butyldimethylsilyl) and aryl-lower alkyl (forexample benzyl) groups.

Examples of amino protecting groups include formyl, aryl-lower alkylgroups (for example benzyl and substituted benzyl, 4-methoxybenzyl,2-nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl);di-4-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (forexample tert-butoxycarbonyl); lower alkenyloxycarbonyl (for exampleallyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for examplebenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyland 4-nitrobenzyloxycarbonyl); trialkylsilyl (for example trimethylsilyland tert-butyldimethylsilyl); alkylidene (for example methylidene) andbenzylidene and substituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groupsinclude, for example, acid-, base-, metal- or enzymically-catalysedhydrolysis for groups such as 2-nitrobenzyloxycarbonyl, hydrogenationfor groups such as benzyl and photolytically for groups such as2-nitrobenzyloxycarbonyl.

The reader is referred to Advanced Organic Chemistry, 4th Edition, by J.March, published by John Wiley & Sons 1992, for general guidance onreaction conditions and reagents and to Protective Groups in OrganicSynthesis, 2^(nd) Edition, by T. Green et al., also published by JohnWiley & Son, for general guidance on protecting groups.

Quinoline starting materials of the Formula II may be obtained byconventional procedures such as those disclosed in International PatentApplications WO 98/43960 and WO 00/68201. For example, a1,4-dihydroquinolin-4-one of Formula IV

wherein m and R¹ have any of the meanings defined hereinbefore exceptthat any functional group is protected if necessary, may be reacted witha halogenating agent such as thionyl chloride, phosphoryl chloride or amixture of carbon tetrachloride and triphenylphosphine whereafter anyprotecting group that is present is removed by conventional means.

The 4-chloroquinoline so obtained may be converted, if required, into a4-pentafluorophenoxyquinoline by reaction with pentafluorophenol in thepresence of a suitable base such as potassium carbonate and in thepresence of a suitable solvent such as N,N-dimethylformamide.

2,3-Methylenedioxyanilino starting materials (Formula III, for examplewhen Z is NH) may be obtained by conventional procedures as illustratedin the Examples. Corresponding 2,3-methylenedioxyphenol and2,3-methylenedioxythiophenol starting materials (Formula III, when Z isO or S) may be obtained by conventional procedures.

-   (b) For the production of those compounds of the Formula I wherein    at least one R¹ group is a group of the formula    Q¹-X¹—    wherein Q¹ is an aryl-(1–6C)alkyl, (3–7C)cycloalkyl-(1–6C)alkyl,    (3–7C)cycloalkenyl-(1–6C)alkyl, heteroaryl-(1–6C)alkyl or    heterocyclyl-(1–6C)alkyl group or an optionally substituted alkyl    group and X¹ is an oxygen atom, the coupling, conveniently in the    presence of a suitable dehydrating agent, of a quinoline of the    Formula V

wherein m, R¹, Z¹, n, R³, Z² and R¹⁴ have any of the meanings definedhereinbefore except that any functional group is protected if necessary,with an appropriate alcohol of the formula Q¹-OH wherein any functionalgroup is protected if necessary, whereafter any protecting group that ispresent is removed by conventional means.

A suitable dehydrating agent is, for example, a carbodiimide reagentsuch as dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or a mixture of an azocompound such as diethyl or di-tert-butyl azodicarboxylate and aphosphine such as triphenylphosphine. The reaction is convenientlycarried out in the presence of a suitable inert solvent or diluent, forexample a halogenated solvent such as methylene chloride, chloroform orcarbon tetrachloride and at a temperature in the range, for example, 10to 150° C., preferably at or near ambient temperature.

The reaction is conveniently carried out in the presence of a suitableinert solvent or diluent, for example a halogenated solvent such asmethylene chloride, chloroform or carbon tetrachloride and at atemperature in the range, for example, 10 to 150° C., preferably at ornear ambient temperature.

-   (c) For the production of those compounds of the Formula I wherein    R¹ is an amino-substituted (1–6C)alkoxy group (such as    2-homopiperidin-1-ylethoxy or 3-dimethylaminopropoxy), the reaction    of a compound of the Formula I wherein R¹ is a halogeno-substituted    (1–6C)alkoxy group with a heterocyclyl compound or an appropriate    amine. The reaction is conveniently carried out in the presence of a    suitable inert diluent or carrier as defined hereinbefore and at a    temperature in the range 10 to 150° C., preferably at or near    ambient temperature.-   (d) For the production of those compounds of the Formula I wherein    an R¹ group contains a (1–6C)alkoxy or substituted (1–6C)alkoxy    group or a (1–6C)alkylamino or substituted (1–6C)alkylamino group,    the alkylation, conveniently in the presence of a suitable base as    defined hereinbefore, of a quinoline derivative of the Formula I    wherein the R¹ group contains hydroxy group or a primary or    secondary amino group as appropriate.

A suitable alkylating agent is, for example, any agent known in the artfor the alkylation of hydroxy to alkoxy or substituted alkoxy, or forthe alkylation of amino to alkylamino or substituted alkylamino, forexample an alkyl or substituted alkyl halide, for example a (1–6C)alkylchloride, bromide or iodide or a substituted (1–6C)alkyl chloride,bromide or iodide, conveniently in the presence of a suitable base asdefined hereinbefore, in a suitable inert solvent or diluent as definedhereinbefore and at a temperature in the range, for example, 10 to 140°C., conveniently at or near ambient temperature.

Conveniently for the production of those compounds of the Formula Iwherein R¹ contains a (1–6C)alkylamino or substituted (1–6C)alkylaminogroup, a reductive amination reaction may be employed. For example, forthe production of those compounds of the Formula I wherein R¹ contains aN-methyl group, the corresponding compound containing a N—H group may bereacted with formaldehyde in the presence of a suitable reducing agent.A suitable reducing agent is, for example, a hydride reducing agent, forexample an alkali metal aluminium hydride such as lithium aluminiumhydride or, preferably, an alkali metal borohydride such as sodiumborohydride, sodium cyanoborohydride, sodium triethylborohydride, sodiumtrimethoxyborohydride and sodium triacetoxyborohydride. The reaction isconveniently performed in a suitable inert solvent or diluent, forexample tetrahydrofuran and diethyl ether for the more powerful reducingagents such as lithium aluminium hydride, and, for example, methylenechloride or a protic solvent such as methanol and ethanol for the lesspowerful reducing agents such as sodium triacetoxyborohydride and sodiumcyanoborohydride. The reaction is performed at a temperature in therange, for example, 10 to 80° C., conveniently at or near ambienttemperature.

-   (e) For the production of those compounds of the Formula I wherein    Z¹ is a SO or SO₂ group, wherein an R¹ or R³ substituent is a    (1–6C)alkylsulphinyl or (1–6C)alkylsulphonyl group or wherein an R¹,    R³ or R¹⁴ substituent contains a SO or SO₂ group, the oxidation of a    compound of Formula I wherein Z¹ is a S group or wherein an R¹ or R³    substituent is a (1–6C)alkylthio group or wherein an R¹, R³ or R¹⁴    substituent contains a S group as appropriate.

Conventional oxidation reagents and reaction conditions for such partialor complete oxidation of a sulphur atom are well known to the organicchemist.

-   (f) The reaction, conveniently in the presence of a suitable base as    defined hereinbefore and in the presence of a suitable catalyst, of    a compound of the Formula VI

wherein L is a displaceable group as defined hereinbefore and m, R¹, Z¹,n and R³ have any of the meanings defined hereinbefore except that anyfunctional group is protected if necessary, with a compound of theFormula VIIHZ²-R¹⁴  VIIwherein Z² is a C≡C or C(R³)═C(R¹³) group and R¹³ and R¹⁴ have any ofthe meanings defined hereinbefore except that any functional group isprotected if necessary, whereafter any protecting group that is presentis removed by conventional means.

Conveniently the displaceable group is a halogeno group such as iodo,bromo or chloro. A suitable catalyst is, for example, an organometallicreagent, for example an organopalladium compound such astetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) dichloride. The conversion reactionis conveniently carried out in the presence of a suitable inert diluentor carrier as defined hereinbefore and at a temperature in the range 10to 150° C., preferably at or near 60° C.

-   (g) For the production of a compound of the Formula I wherein R¹⁴ is    a carboxy group, the cleavage of a compound of the Formula I wherein    R¹⁴ is a (1–6C)alkoxycarbonyl group.

The cleavage reaction is conveniently carried out by the hydrolysis ofthe (1–6C)alkoxycarbonyl group in the presence of a suitable base, forexample an alkali or alkaline earth metal carbonate or hydroxide such assodium carbonate, potassium carbonate, calcium carbonate, sodiumhydroxide or potassium hydroxide and in the presence of a suitable inertdiluent or carrier as defined hereinbefore such as methanol and at atemperature in the range 10 to 150° C., preferably at or near 40° C.

-   (h) The reaction, conveniently in the presence of a suitable    dehydrating agent as defined hereinbefore, of a compound of the    Formula I wherein R¹⁴ is a carboxy group with an appropriate amine    to form a further compound of the Formula I wherein R¹⁴ is a    carbamoyl, N-(1–6C)alkylcarbamoyl, N,N-di-[(1–6C)alkyl]carbamoyl or    heterocyclylcarbonylamino group.

The reaction is conveniently carried out in the presence of a suitableinert diluent or carrier as defined hereinbefore and at a temperature inthe range, for example, 10 to 150° C., preferably at or near ambienttemperature.

When a pharmaceutically-acceptable salt of a quinoline derivative of theFormula I is required; for example an acid-addition salt, it may beobtained by, for example, reaction of said quinoline derivative with asuitable acid using a conventional procedure.

Biological Assays

The following assays can be used to measure the effects of the compoundsas inhibitors of the MAPK pathway.

(a) Assay to Detect MEK Inhibition

To evaluate inhibitors of the MAPK pathway, a coupled assay was carriedout which measures phosphorylation of serine/threonine residues presentin the substrate in the presence or absence of inhibitor. Recombinantglutathione S-transferase fusion protein containing human p45MEK1(GST-MEK) was activated by c-raf (Sf9 insect cell lysate from triplebaculoviral infection with c-raf/ras/lck) and used for the assay. ActiveGST-MEK was first used to activate a recombinant glutathioneS-transferase fusion protein containing p44MAP kinase (GST-MAPK) in thepresence of ATP and Mg²⁺ for 60 minutes at room temperature in thepresence or absence of potential inhibitors. The activated GST-MAPK wasthen incubated with myelin basic protein (MBP) as substrate for 10minutes at room temperature in the presence of ATP, Mg²⁺ and ³³P-ATP.The reaction was stopped by addition of 20% v/v phosphoric acid.Incorporation of ³³P into the myelin basic protein was determined bycapture of the substrate on a filter mat, washing and counting usingscintillation methods. The extent of inhibition was determined bycomparison with untreated controls.

The final assay solution contained 10 mM Tris, pH 7.5, 0.05 mM EGTA,8.33 μM [γ³³P]ATP, 8.33 mM Mg(OAc)₂, 0.5 mM sodium orthovanadate, 0.05%w/v BSA, 6.5 ng GST-MEK, log GST-MAPK and 16.5 μg MBP in a reactionvolume of 60 μl.

(b) In Vitro MAP Kinase Assay

To determine whether compounds were inhibiting GST-MEK or GST-MAPK, adirect assay of MAPK activity was employed. GST-MAPK was activated by aconstitutively active GST-MEK fusion protein containing two pointmutations (S217E, S221E) and used for the assay in the presence andabsence of potential inhibitors. The activated GST-MAPK was incubatedwith substrate (MBP) for 60 min at room temperature in the presence ofATP, Mg²⁺ and ³³P-ATP. The reaction was stopped by addition of 20% v/vphosphoric acid. Incorporation of ³³P into the myelin basic protein wasdetermined by capture of the substrate on a filter mat, washing andcounting using scintillation methods.

The final assay solution contained 12 mM Tris, pH 7.5, 0.06 mM EGTA, 30μM [γ³³P]ATP, 10 mM Mg(OAc)₂, 0.6 mM sodium orthovanadate, 0.06% w/vBSA, 28 ng GST-MAPK and 16.5 μg MBP in a reaction volume of 60 μl;

(c) Cell Proliferation Assays

Cells were seeded into multi-well plates at 20,000–40,000 cells/ml ingrowth medium containing 5% FCS and incubated overnight at 37° C. Thecompounds were prepared in fresh medium at an appropriate concentrationand added to the wells containing the cells. These were then incubatedfor a further 72 hours. Cells were then either removed from the wells byincubating with trypsin/EDTA and counted using a Coulter counter, ortreated with XTT/PMS in PBSA and optical densities read at 450 nm.

The following assays can be used to measure the effects of the compoundsof the present invention as c-Src tyrosine kinase inhibitors, asinhibitors in vitro of the proliferation of c-Src transfected fibroblastcells, as inhibitors in vitro of the migration of A549 human lung tumourcells and as inhibitors in vivo of the growth in nude mice of xenograftsof A549 tissue.

(d) In Vitro Src Enzyme Assay

The ability of test compounds to inhibit the phosphorylation of atyrosine containing polypeptide substrate by the enzyme c-Src kinase wasassessed using a conventional Elisa assay.

A substrate solution [100 μl of a 20 μg/ml solution of the polyaminoacid Poly(Glu, Tyr) 4:1 (Sigma Catalogue No. P0275) in phosphatebuffered saline (PBS) containing 0.2 mg/ml of sodium azide] was added toeach well of a number of Nunc 96-well immunoplates (Catalogue No.439454) and the plates were sealed and stored at 4° C. for 16 hours. Theexcess of substrate solution was discarded, and aliquots of Bovine SerumAlbumin (BSA; 150 μl of a 5% solution in PBS) were transferred into eachsubstrate-coated assay well and incubated for 1 hour at ambienttemperature to block non specific binding. The assay plate wells werewashed in turn with PBS containing 0.05% v/v Tween 20 (PBST) and withHepes pH7.4 buffer (50 mM, 300 μl/well) before being blotted dry.

Each test compound was dissolved in dimethyl sulphoxide and diluted withdistilled water to give a series of dilutions (from 100 μM to 0.001 μM).Portions (25 μl) of each dilution of test compound were transferred towells in the washed assay plates. “Total” control-wells containeddiluted DMSO instead of compound. Aliquots (25 μl) of an aqueousmagnesium chloride solution (80 mM) containing adenosine-5′-triphosphate(ATP; 40 μM) was added to all test wells except the “blank” controlwells which contained magnesium chloride without ATP.

Active human c-Src kinase (recombinant enzyme expressed in Sf9 insectcells; obtained from Upstate Biotechnology Inc. product 14–117) wasdiluted immediately prior to use by a factor of 1:10,000 with an enzymediluent which comprised 100 mM Hepes pH7.4 buffer, 0.2 mM sodiumorthovanadate, 2 mM dithiothreitol and 0.02% BSA. To start thereactions, aliquots (50 μl) of freshly diluted enzyme were added to eachwell and the plates were incubated at ambient temperature for 20minutes. The supernatant liquid in each well was discarded and the wellswere washed twice with PBST. Mouse IgG anti-phosphotyrosine antibody(Upstate Biotechnology Inc. product 05–321; 100 μl) was diluted by afactor of 1:6000 with PBST containing 0.5% w/v BSA and added to eachwell. The plates were incubated for 1 hour at ambient temperature. Thesupernatant liquid was discarded and each well was washed with PBST(×4). Horse radish peroxidase (HRP)-linked sheep anti-mouse Ig antibody(Amersham Catalogue No. NXA 931; 100 μl) was diluted by a factor of1:500 with PBST containing 0.5% w/v BSA and added to each well. Theplates were incubated for 1 hour at ambient temperature. The supernatantliquid was discarded and the wells were washed with PBST (×4).

A PCSB capsule (Sigma Catalogue No. P4922) was dissolved in distilledwater (100 ml) to provide phosphate-citrate pH5 buffer (50 mM)containing 0.03% sodium perborate. An aliquot (50 ml) of this buffer wasmixed with a 50 mg tablet of2,2′-azinobis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS; BoehringerCatalogue No. 1204 521). Aliquots (100 μL) of the resultant solutionwere added to each well. The plates were incubated for 20 to 60 minutesat ambient temperature until the optical density value of the “total”control wells, measured at 405 nm using a plate readingspectrophotometer, was approximately 1.0. “Blank” (no ATP) and “total”(no compound) control values were used to determine the dilution rangeof test compound which gave 50% inhibition of enzyme activity.

(e) In Vitro c-Src Transfected NIH 3T3 (c-src 3T3) FibroblastProliferation Assay

This assay determined the ability of a test compound to inhibit theproliferation of National Institute of Health (NIH) mouse 3T3 fibroblastcells that had been stably-transfected with an activating mutant (Y530F)of human c-Src.

Using a similar procedure to that described by Shalloway et al., Cell,1987, 49, 65–73, NIH 3T3 cells were transfected with an activatingmutant (Y530F) of human c-Src. The resultant c-Src 3T3 cells weretypically seeded at 1.5×10⁴ cells per well into 96-welltissue-culture-treated clear assay plates (Costar) each containing anassay medium comprising Dulbecco's modified Eagle's medium (DMEM; Sigma)plus 0.5% foetal calf serum (FCS), 2 mM glutamine, 100 units/mlpenicillin and 0.1 mg/ml streptomycin in 0.9% aqueous sodium chloridesolution. The plates were incubated overnight at 37° C. in a humidified(7.5% CO₂: 95% air) incubator.

Test compounds were solubilised in DMSO to form a 10 mM stock solution.Aliquots of the stock solution were diluted with the DMEM mediumdescribed above and added to appropriate wells. Serial dilutions weremade to give a range of test concentrations. Control wells to which testcompound was not added were included on each plate. The plates wereincubated overnight at 37° C. in a humidified (7.5% CO₂: 95% air)incubator.

BrdU labelling reagent (Boehringer Mannheim Catalogue No. 647 229) wasdiluted by a factor of 1:100 in DMEM medium containing 0.5% FCS andaliquots (20 μl) were added to each well to give a final concentrationof 10 μl). The plates were incubated at 37° C. for 2 hours. The mediumwas decanted. A denaturating solution (FixDenat solution, BoehringerMannheim Catalogue No. 647 229; 50 μl) was added to each well and theplates were placed on a plate shaker at ambient temperature for 45minutes. The supernatant was decanted and the wells were washed with PBS(200 μl per well). Anti-BrdU-Peroxidase solution (Boehringer MannheimCatalogue No. 647 229) was diluted by a factor of 1:100 in PBScontaining 1% BSA and 0.025% dried skimmed milk (Marvel (registeredtrade mark), Premier Beverages, Stafford, GB) and an aliquot (100 μl) ofthe resultant solution was added to each well. The plates were placed ona plate shaker at ambient temperature for 90 minutes. The wells werewashed with PBS (×5) to ensure removal of non-bound antibody conjugate.The plates were blotted dry and tetramethylbenzidine substrate solution(Boehringer Mannheim Catalogue No. 647 229; 100 μl) was added to eachwell. The plates were gently agitated on a plate shaker while the colourdeveloped during a 10 to 20 minute period. The absorbance of the wellswas measured at 690 nm. The extent of inhibition of cellularproliferation at a range of concentrations of each test compound wasdetermined and an anti-proliferative IC₅₀ value was derived.

(f) In Vitro Microdroplet Migration Assay

This assay determines the ability of a test compound to inhibit themigration of adherent mammalian cell lines, for example the human tumourcell line A549.

RPMI medium(Sigma) containing 10% FCS, 1% L-glutamine and 0.3% agarose(Difco Catalogue No. 0142-01) was warmed to 37° C. in a water bath. Astock 2% aqueous agar solution was autoclaved and stored at 42° C. Analiquot (1.5 ml) of the agar solution was added to RPMI medium (10 ml)immediately prior to its use. A549 cells (Accession No. ATCC CCL185)were suspended at a concentration of 2×10⁷ cells/ml in the medium andmaintained at a temperature of 37° C.

A droplet (2 μl) of the cell/agarose mixture was transferred by pipetteinto the centre of each well of a number of 96-well, flat bottomednon-tissue-culture-treated microtitre plate (Bibby Sterilin CatalogueNo. 642000). The plates were placed briefly on ice to speed the gellingof the agarose-containing droplets. Aliquots (90 μl) of medium which hadbeen cooled to 4° C. were transferred into each well, taking care not todisturb the microdroplets. Test compounds were diluted from a 10 mMstock solution in DMSO using RPMI medium as described above. Aliquots(10 μl) of the diluted test compounds were transferred to the wells,again taking care not to disturb the microdroplets. The plates wereincubated at 37° C. in a humidified (7.5% CO₂: 95% air) incubator forabout 48 hours.

Migration was assessed visually and the distance of migration wasmeasured back to the edge of the agar droplet. A migratory inhibitoryIC₅₀ was derived by plotting the mean migration measurement against testcompound concentration.

(g) In Vivo A549 Xenograft Growth Assay

This test measures the ability of compounds to inhibit the growth of theA549 human carcinoma grown as a tumour in athymic nude mice (AlderleyPark nu/nu strain). A total of about 5×10⁶ A549 cells in matrigel(Beckton Dickinson Catalogue No. 40234) were injected subcutaneouslyinto the left flank of each test mouse and the resultant tumours wereallowed to grow for about 14 days. Tumour size was measured twice weeklyusing callipers and a theoretical volume was calculated. Animals wereselected to provide control and treatment groups of approximately equalaverage tumour volume. Test compounds were prepared as a ball-milledsuspension in 1% polysorbate vehicle and dosed orally once daily for aperiod of about 28 days. The effect on tumour growth was assessed.

Although the pharmacological properties of the compounds of the FormulaI vary with structural change as expected, in general activity possessedby compounds of the Formula I, may be demonstrated at the followingconcentrations or doses in one or more of the above tests (a) to (g):

Test (a):—IC₅₀ in the range, for example, less than 4 μM;

Test (b):—activity was observed in this screen;

Test (c):—IC₅₀ in the range, for example, less than 30 μM.

Test (d):—IC₅₀ in the range, for example, 0.001–10 μM;

Test (d):—IC₅₀ in the range, for example, 0.01–20 μM;

Test (f):—activity in the range, for example, 0.1–25 μM;

Test (g):—activity in the range, for example, 1–200 mg/kg/day;

No physiologically-unacceptable toxicity was observed in Test (g) at theeffective dose for compounds tested of the present invention.Accordingly no untoward toxicological effects are expected when acompound of Formula I, or a pharmaceutically-acceptable salt thereof, asdefined hereinbefore is administered at the dosage ranges definedhereinafter.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a quinoline derivative of theFormula I, or a pharmaceutically-acceptable salt thereof, as definedhereinbefore in association with a pharmaceutically-acceptable diluentor carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, forexample from 1 to 30 mg) compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition.

The size of the dose for therapeutic or prophylactic purposes of acompound of the Formula I will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine.

In using a compound of the Formula I for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.1 mg/kg to 75 mg/kg body weight is received, givenif required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous administration, a dose in the range, for example, 0.1 mg/kgto 30 mg/kg body weight will generally be used. Similarly, foradministration by inhalation, a dose in the range, for example, 0.05mg/kg to 25 mg/kg body weight will be used. Oral administration ishowever preferred, particularly in tablet form. Typically, unit dosageforms will contain about 0.5 mg to 0.5 g of a compound of thisinvention.

According to a further aspect of the invention there is provided aquinoline derivative of the Formula I, or a pharmaceutically-acceptablesalt thereof, as defined hereinbefore for use in a method of treatmentof the human or animal body by therapy.

According to a further aspect of the invention there is provided aquinoline derivative of the Formula I, or a pharmaceutically-acceptablesalt thereof, as defined hereinbefore for use in the treatment orcancer.

As stated above we have also found that the quinoline derivatives of thepresent invention of Formula I possess potent anti-tumour activity whichit is believed is obtained by way of inhibition of one or more of theMEK enzymes that are involved in the MAPK pathway.

Accordingly, the quinoline derivatives of Formula I are of value asanti-proliferative agents in the containment and/or treatment of solidtumour disease. Particularly, the compounds of Formula I are expected tobe useful in the prevention or treatment of those tumours which aresensitive to inhibition of one or more of the MEK enzymes that areinvolved in the MAPK pathway. Further, the compounds of Formula I areexpected to be useful in the prevention or treatment of those tumourswhich are mediated alone or in part by inhibition of the MEK enzymesi.e. the compounds may be used to produce a MEK enzyme inhibitory effectin a warm-blooded animal in need of such treatment. Specifically, thecompounds of Formula I are expected to be useful in the prevention ortreatment of solid tumour disease.

Thus, according to this aspect of the invention there is provided of aquinoline derivative of the Formula I, or a pharmaceutically-acceptablesalt thereof, as defined hereinbefore for use as an anti-proliferativeagent in the containment and/or treatment of solid tumour disease.

According to a farther aspect of the invention there is provided the useof a quinoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use as an anti-proliferative agent inthe containment and/or treatment of solid tumour disease.

According to a further feature of the invention there is provided amethod for producing an anti-proliferative effect by the containmentand/or treatment of solid tumour disease in a warm-blooded animal, suchas man, in need of such treatment which comprises administering to saidanimal an effective amount of a quinoline derivative of the Formula I,or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect of the invention there is provided the useof a quinoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use in the prevention or treatment ofsolid tumour disease in a warm-blooded animals such as man.

According to a further feature of this aspect of the invention there isprovided a method for the prevention or treatment of solid tumourdisease in a warm-blooded animal, such as man, in need of such treatmentwhich comprises administering to said animal an effective amount of aquinoline derivative of the Formula 1, or a pharmaceutically-acceptablesalt thereof as defined hereinbefore.

According to a further aspect of the invention there is provided the useof a quinoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use in the prevention or treatment ofthose tumours which are sensitive to inhibition of MEK enzymes that areinvolved in the MAPK pathway. Particular enzymes that the tumours may besensitive to are MEK 1, MEK 2 and MEK 5.

According to a further feature of this aspect of the invention there isprovided a method for the prevention or treatment of those tumours whichare sensitive to inhibition of MEK enzymes that are involved in the MAPKpathway which comprises administering to said animal an effective amountof a quinoline derivative of the Formula L or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect of the invention there is provided the useof a quinoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use in providing a MEK enzyme inhibitoryeffect.

According to a further feature of this aspect of the invention there isprovided a method for providing a MEK enzyme inhibitory effect whichcomprises administering to said animal an effective amount of aquinoline derivative of the Formula I, or a pharmaceutically-acceptablesalt thereof, as defined hereinbefore.

We have also found that the quinoline derivatives of the presentinvention possess potent anti-tumour activity which it is believed isobtained by way of inhibition of one or more of the non-receptortyrosine-specific protein kinases such as c-Src kinase that are involvedin the signal transduction steps which lead to the invasiveness andmigratory ability of metastasising tumour cells.

Particularly, the quinoline derivatives of the present invention are ofvalue as anti-invasive agents in the containment and/or treatment ofsolid tumour disease. Particularly, the compounds of the presentinvention are expected to be useful in the prevention or treatment ofthose tumours which are sensitive to inhibition of one or more of themultiple non-receptor tyrosine kinases such as c-Src kinase that areinvolved in the signal transduction steps which lead to the invasivenessand migratory ability of metastasising tumour cells. Further, thecompounds of the present invention are expected to be useful in theprevention or treatment of those tumours which are mediated alone or inpart by inhibition of the enzyme c-Src, i.e. the compounds may be usedto produce a c-Src enzyme inhibitory effect in a warm-blooded animal inneed of such treatment. Specifically, the compounds of the presentinvention are expected to be useful in the prevention or treatment ofsolid tumour disease.

According to this aspect of the invention there is provided a quinolinederivative of the Formula I, or a pharmaceutically-acceptable saltthereof, as defined hereinbefore for use as an anti-invasive agent inthe containment and/or treatment of solid tumour disease.

According to a further feature of this aspect of the invention there isprovided the use of a quinoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use as an anti-invasive agent in thecontainment and/or treatment of solid tumour disease.

According to a further feature of this aspect of the invention there isprovided a method for producing an anti-invasive effect by thecontainment and/or treatment of solid tumour disease in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a quinolinederivative of the Formula I, or a pharmaceutically-acceptable saltthereof, as defined hereinbefore.

According to a further aspect of the invention there is provided the useof a quinoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use in the prevention or treatment ofthose tumours which are sensitive to inhibition of non-receptor tyrosinekinases such as c-Src kinase that are involved in the signaltransduction steps which lead to the invasiveness and migratory abilityof metastasising tumour cells.

According to a further feature of this aspect of the invention there isprovided a method for the prevention or treatment of those tumours whichare sensitive to inhibition of non-receptor tyrosine kinases such asc-Src kinase that are involved in the signal transduction steps whichlead to the invasiveness and migratory ability of metastasising tumourcells which comprises administering to said animal an effective amountof a quinoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect of the invention there is provided the useof a quinoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use in providing a c-Src kinaseinhibitory effect.

According to a further feature of this aspect of the invention there isprovided a method for providing a c-Src kinase inhibitory effect whichcomprises administering to said animal an effective amount of aquinoline derivative of the Formula I, or a pharmaceutically-acceptablesalt thereof, as defined hereinbefore.

The anti-proliferative and anti-invasive treatment defined hereinbeforemay be applied as a sole therapy or may involve, in addition to thequinoline derivative of the invention, conventional surgery orradiotherapy or chemotherapy. Such chemotherapy may include one or moreof the following categories of anti-tumour agents:

-   (i) other anti-invasion agents (for example metalloproteinase    inhibitors like marimastat and inhibitors of urokinase plasminogen    activator receptor function);-   (ii) other anti-proliferative or antineoplastic drugs and    combinations thereof, as used in medical oncology, such as    alkylating agents (for example cis-platin, carboplatin,    cyclophosphamide, nitrogen mustard, melphalan, chlorambucil,    busulphan and nitrosoureas); antimetabolites (for example    antifolates such as fluoropyrimidines like 5-fluorouracil and    tegafur, raltitrexed, methotrexate, cytosine arabinoside and    hydroxyurea, or, for example, one of the preferred antimetabolites    disclosed in European Patent Application No. 562734 such as    (2S)-2-{o-fluoro-p-[N-{2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzamido}-4-(tetrazol-5-yl)butyric    acid); antitumour antibiotics (for example anthracyclines like    adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin,    idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic    agents (for example vinca alkaloids like vincristine, vinblastine,    vindesine and vinorelbine and taxoids like taxol and taxotere); and    topoisomerase inhibitors (for example epipodophyllotoxins like    etoposide and teniposide, amsacrine, topotecan and camptothecin);-   (iii) cytostatic agents such as antioestrogens (for example    tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene),    antiandrogens (for example bicalutamide, flutamide, nilutamide and    cyproterone acetate), LHRH antagonists or LHRH agonists (for example    goserelin, leuprorelin and buserelin), progestogens (for example    megestrol acetate), aromatase inhibitors (for example as    anastrozole, letrazole, vorazole and exemestane) and inhibitors of 5    α-reductase such as finasteride;-   (iv) inhibitors of growth factor function, for example such    inhibitors include growth factor antibodies, growth factor receptor    antibodies, farnesyl transferase inhibitors, tyrosine kinase    inhibitors and serine/threonine kinase inhibitors, for example    inhibitors of the epidermal growth factor family (for example the    EGFR tyrosine kinase inhibitors    N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine    (ZD1839),    N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine    (CP 358774) and    6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine    (CI 1033)), for example inhibitors of the platelet-derived growth    factor family and for example inhibitors of the hepatocyte growth    factor family;-   (v) antiangiogenic agents such as those which inhibit vascular    endothelial growth factor such as the compounds disclosed in    International Patent Applications WO 97/22596, WO 97/30035, WO    97/32856 and WO 98/13354 and those that work by other mechanisms    (for example linomide, inhibitors of integrin αvβ₃ function and    angiostatin);-   (vi) antisense therapies, for example those which are directed to    the targets listed above, such as ISIS 2503, an anti-ras antisense;-   (vii) gene therapy approaches, including for example approaches to    replace aberrant genes such as aberrant p53 or aberrant BRCA1, GDEPT    (gene-directed enzyme pro-drug therapy) approaches such as those    using cytosine deaminase, thymidine kinase or a bacterial    nitroreductase enzyme and approaches to increase patient tolerance    to chemotherapy or radiotherapy such as multi-drug resistance gene    therapy; and-   (viii) immunotherapy approaches, including for example ex-vivo and    in-vivo approaches to increase the immunogenicity of patient tumour    cells, such as transfection with cytokines such as interleukin 2,    interleukin 4 or granulocyte-macrophage colony stimulating factor,    approaches to decrease T-cell anergy, approaches using transfected    immune cells such as cytokine-transfected dendritic cells,    approaches using cytokine-transfected tumour cell lines and    approaches using anti-idiotypic antibodies.

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention within the dosage range described hereinbefore and the otherpharmaceutically-active agent within its approved dosage range.

According to this aspect of the invention there is provided apharmaceutical product comprising a quinoline derivative of the formulaI as defined hereinbefore and an additional anti-tumour agent as definedhereinbefore for the conjoint treatment of cancer.

Although the compounds of the Formula I are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the effects of theMEK enzymes that are involved in the MAPK kinase pathway or the effectsof c Src. Thus, they are useful as pharmacological standards for use inthe development of new biological tests and in the search for newpharmacological agents.

The invention will now be illustrated in the following Examples inwhich, generally:

(i) operations were carried out at ambient temperature, i.e. in therange 17 to 25° C. and under an atmosphere of an inert gas such as argonunless otherwise stated;

(ii) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;

(iii) column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC) were performed on Merck Kieselgel silica(Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silicaobtained from E. Merck, Darmstadt, Germany or high pressure liquidchromatography (HPLC) was performed on C18 reverse phase silica, forexample on a Dynamax C-18 60 Å preparative reversed-phase column;

(iv) yields, where present, are not necessarily the maximum attainable;

(v) in general, the end-products of the Formula I have satisfactorymicroanalyses and their structures were confirmed by nuclear magneticresonance (NMR) and/or mass spectral techniques; fast-atom bombardment(FAB) mass spectral data were obtained using a Platform spectrometerand, Where appropriate, either positive ion data or negative ion datawere collected; NMR chemical shift values were measured on the deltascale [proton magnetic resonance spectra were determined using a JeolJNM EX 400 spectrometer operating at a field strength of 400 MHz, VarianGemini 2000 spectrometer operating at a field strength of 300 MHz or aBruker AM300 spectrometer operating at a field strength of 300 MHz]; thefollowing abbreviations have been used: s, singlet; d, doublet; t,triplet; q, quartet; m, multiplet; br, broad;

(vi) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatographic, HPLC, infra-red (IR) and/or NMRanalysis;

(vii) melting points are uncorrected and were determined using a MettlerSP62 automatic melting point apparatus or an oil-bath apparatus; meltingpoints for the end-products of the Formula I were determined aftercrystallisation from a conventional organic solvent such as ethanol,methanol, acetone, ether or hexane, alone or in admixture;

(viii) the following abbreviations have been used:

-   -   DMF N,N-dimethylform amide    -   DMSO dimethylsulphoxide    -   THF tetrahydrofuran

EXAMPLE 13-cyano-6,7-dimethoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinolinemonohydrochloride salt

A mixture of3-cyano-4-(4-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinoline (0.2g), methyl 2-propynyl ether (0.071 ml),tetrakis(triphenylphosphine)palladium(0) (0.05 g), cuprous iodide (0.01g) and N,N-diethylamine (4 ml) was stirred and heated to 60° C. for 4hours. The reaction mixture was evaporated and the residue waspartitioned between methylene chloride and a 2N aqueous hydrochloricacid solution. The precipitate that was formed was isolated byfiltration, washed in turn with methylene chloride, ethanol and diethylether and dried. There was thus obtained the title compound (0.085 g);NMR Spectrum: (DMSOd₆) 3.33 (s, 3H), 3.98 (s, 3H), 3.99 (s, 3H), 4.36(s, 2H), 6.12 (s, 2H), 6.98 (d, 1H), 7.02 (d, 1H), 7.47 (s, 1H), 8.13(s, 1H), 8.98 (s, 1H); Mass Spectrum: M+H⁺ 418.

The 3-cyano-4-(4-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinolineused as a starting material was prepared as follows:

Sodium hexamethyldisilazane (1M solution in THF; 3.8 ml) was added to asolution of 4-iodo-2,3-methylenedioxyaniline (0.5 g) in DMF (1.2 ml)that was cooled to 0° C. and the mixture was stirred for 5 minutes. Asolution of 4-chloro-3-cyano-6,7-dimethoxyquinoline (InternationalPatent Application WO 98/43960; 0.43 g) in DMF (3 ml) was added and theresultant mixture was stirred at ambient temperature for 2 hours. Thereaction mixture was diluted with water and extracted with ethylacetate. The organic phase was washed with water and with a saturatedbrine solution, dried over magnesium sulphate and evaporated. Theresidue was purified by column chromatography on silica increasinglypolar mixtures of methylene chloride and ethyl acetate as eluent. Therewas thus obtained3-cyano-4-(4-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinoline as asolid (0.8 g); NMR Spectrum: (DMSOd⁶) 3.77 (s, 3H), 3.81 (s, 3H), 5.88(s, 2H), 6.3 (d, 1H), 6.87 (d, 1H), 6.93 (s, 1H), 7.7 (s, 1H), 7.83 (s,1H); Mass Spectrum: M+H⁺ 476.

The 4-iodo-2,3-methylenedioxyaniline used as a starting material wasprepared as follows:

A mixture of 2,3-dihydroxybenzoic acid (5 g), methanol (50 ml) andconcentrated sulphuric acid (10 drops) was stirred and heated to 60° C.for 24 hours. The mixture was evaporated and the residue was taken up inethyl acetate. The organic solution was washed with a saturated solutionof sodium bicarbonate, dried over magnesium sulphate and evaporated togive methyl 2,3-dihydroxybenzoate (2.19 g); NMR Spectrum: (CDCl₃) 3.95(s, 3H), 5.7 (s, 1H), 6.8 (t, 1H), 7.15 (d, H), 7.35 (d, H).

After repetition of the previous reaction, a mixture of methyl2,3-dihydroxybenzoate (2.8 g), potassium fluoride (4.8 g) and DMF (45ml) was stirred at ambient temperature for 30 minutes. Dibromomethane(1.28 ml) was added and the mixture was heated to 120° C. for 3 hours.The mixture was cooled to ambient temperature, poured into water andextracted with diethyl ether. The organic phase was washed with waterand with a saturated brine solution, dried over magnesium sulphate andevaporated. The residue was purified by column chromatography using a9:1 mixture of petroleum ether (b.p. 40–60° C.) and ethyl acetate aseluent. There was thus obtained methyl 2,3-methylenedioxybenzoate (2.3g) as a solid; NMR Spectrum: (CDCl₃) 3.95 (s, 3H), 6.1 (s, 2H), 6.85 (t,1H), 7.0 (d, 1H), 7.45 (d, 1H).

A mixture of the material so obtained, a 2N aqueous potassium hydroxidesolution (15.5 ml) and methanol (40 ml) was stirred at ambienttemperature for 2 hours. The solution was concentrated to about onequarter of the original volume and cooled in an ice bath. The mixturewas acidified to pH3.5 by the addition of a 2N aqueous hydrochloric acidsolution. The resultant precipitate was collected by filtration andwashed in turn with water and diethyl ether. There was thus obtained2,3-methylenedioxybenzoic acid (1.87 g); NMR Spectrum: (DMSOd₆) 6.1 (s,1H), 6.9 (t, 1H), 7.15 (d, 1H), 7.3 (d, 1H), 13.0 (br s, 1H).

The material so obtained was suspended in anhydrous dioxane (30 ml) andanhydrous diphenylphosphoryl azide (2.45 ml), triethylamine (1.6 ml) andtert-butanol (9 ml) were added. The mixture was heated to reflux for 5hours. The mixture was cooled to ambient temperature, concentrated byevaporation and diluted with ethyl acetate. The organic phase was washedin turn with a 5% aqueous citric acid solution, water, an aqueous sodiumbicarbonate solution and a saturated brine solution and dried overmagnesium sulphate. The solvent was evaporated and the residue waspurified by column chromatography on silica using a 19:1 mixture ofpetroleum ether (b.p. 40–60° C.) and ethyl acetate as eluent. There wasthus obtained tert-butyl N-(2,3-methylenedioxyphenyl)carbamate (1.98 g)as a solid; NMR Spectrum: (CDCl₃) 1.55 (s, 9H), 5.95 (s, 2H), 6.4 (br s,1H), 6.55 (d, 1H), 6.8 (t, 1H), 7.45 (d, 1H).

A 5N aqueous hydrochloric acid solution (30 ml) was added to a solutionof tert-butyl N-(2,3-methylenedioxyphenyl)carbamate (1.9 g) in ethanol(38 ml) and the reaction mixture was stirred at ambient temperature for20 hours. The ethanol was evaporated and the residual aqueous phase waswashed with diethyl ether and neutralised to pH7 by the addition ofsolid potassium hydroxide. The resultant mixture was filtered and theaqueous phase was extracted with diethyl ether. The organic phase waswashed with a saturated brine solution, dried over magnesium sulphateand evaporated. There was thus obtained 2,3-methylenedioxyaniline (1.0g) as an oil; NMR Spectrum: (CDCl₃) 3.0 (br s, 2H), 5.9 (s, 2H), 6.3 (m,2H), 7.25 (t, 1H).

Benzyltrimethylammonium dichloroiodate (2.8 g) was added portionwiseduring 10 minutes to a stirred mixture of 2,3-methylenedioxyaniline (1g), calcium carbonate (0.95 g), methanol (5 ml) and methylene chloride(10 ml). The reaction mixture was stirred at ambient temperature for 1.5hours. The resultant mixture was diluted with water and extracted withmethylene chloride. The organic phase was washed with water and with asaturated-brine solution, dried over magnesium sulphate and evaporated.The residue was purified by column chromatography on silica usingincreasingly polar mixtures of isohexane, and methylene chloride aseluent. There was thus obtained 4-iodo-2,3-methylenedioxyaniline as asolid (1.1 g); NMR Spectrum: (DMSOd₆) 5.04 (br s, 2H), 5.94 (s, 2H),6.13 (d, 1H), 6.8 (d, 1H).

EXAMPLE 23-cyano-6,7-dimethoxy-4-[6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline

A mixture of4-(6-chloro-4-iodo-2,3-methylenedioxyanilino)-3-cyano-6,7-dimethoxyquinoline(0.25 g), methyl 2-propynyl ether (0.09 ml), N,N-diisopropylamine (0.154ml), bis(triphenylphosphine)palladium(II) dichloride (0.069 g), cuprousiodide (0.028 g) and ethyl acetate (10 ml) was stirred and heated toreflux for 12 hours. The reaction mixture was cooled to ambienttemperature and partitioned between ethyl acetate and water. The organiclayer was dried over magnesium sulphate and evaporated and the residuewas purified by column chromatography on silica using increasingly polarmixtures of hexane and ethyl acetate as eluent. There was thus obtainedthe title compound as an oil (0.138 g); NMR Spectrum: (DMSOd₆) 3.42 (s,3H), 3.97 (s, 3H), 3.99 (s, 3H), 4.38 (s, 2H), 6.17 (s, 2H), 7.13 (s,1H), 7.36 (s, 1H), 7.92 (s, 1H), 8.39 (s, 1H), 9.42 (br s, 1H); MassSpectrum: M+H⁺ 452.

The4-(6-chloro-4-iodo-2,3-methylenedioxyanilino)-3-cyano-6,7-dimethoxyquinolineused as a starting material was prepared as follows:

Using an analogous procedure to that described in the portion of Example1 that is concerned with the preparation of starting materials,4-chloro-3-cyano-6,7-dimethoxyquinoline (1.74 g) was reacted with6-chloro-4-iodo-2,3-methylenedioxyaniline (2.5 g) to give4-(6-chloro-4-iodo-2,3-methylenedioxyanilino)-3-cyano-6,7-dimethoxyquinolineas a solid (2.59 g) which gave the following characterising data; NMRSpectrum: (DMSOd₆) 4.0 (s, 6H), 6.18 (s, 2H), 7.38 (s, 1H), 7.48 (s,1H), 7.88 (s, 1H), 8.44 (s, 1H), 9.45 (s, 1H); Mass Spectrum: M+H⁺ 510.

The 6-chloro-4-iodo-2,3-methylenedioxyaniline used as a startingmaterial was prepared as follows:

Sulphuryl chloride (72.5 ml) was added dropwise during 1.7 hours to astirred mixture of benzodioxole (100 g), aluminium trichloride (0.43 g)and diphenyl sulphide (0.55 ml). Once the reaction started with theevolution of sulphur dioxide, the reaction mixture was cooled in a waterbath to a temperature of approximately 22° C. After completion of theaddition, the reaction mixture was stirred at ambient temperature for 45minutes. The reaction mixture was degassed under vacuum and filtered andthe filtrate was distilled at atmospheric pressure using a Vigreuxdistillation column. There was thus obtained 5-chloro-1,3-benzodioxole;b.p. 185–187° C.; NMR Spectrum: (CDCl₃) 6.0 (s, 2H); 6.7 (d, 1H);6.75–6.9 (m, 2H).

A mixture of diisopropylamine (4.92 ml) and THF (100 ml) was cooled to−78° C. and n-butyllithium (2.5 M in hexane, 14 ml) was added dropwise.The mixture was stirred at −78° C. for 15 minutes.5-Chloro-1,3-benzodioxole (3.73 ml) was added dropwise and the reactionmixture was stirred at −78° C. for 30 minutes. Dry carbon dioxide gaswas bubbled into the reaction mixture for 30 minutes. The resultantreaction mixture was allowed to warm to ambient temperature and wasstirred for a further hour. Water was added and the organic solvent wasevaporated. The residue was acidified to pH2 by the addition of 2Naqueous hydrochloric acid solution. The resultant solid was isolated andwashed in turn with water and diethyl ether. There was thus obtained5-chloro-1,3-benzodioxole-4-carboxylic acid (5.4 g); NMR Spectrum:(DMSOd₆) 6.15 (s, 2H), 7.0 (m, 2H), 13.7 (br s, 1H).

A portion (1 g) of the material so obtained was dissolved in 1,4-dioxane(15 ml) and anhydrous tert-butanol (4 ml), diphenylphosphoryl azide(1.12 ml) and triethylamine (0.73 ml) were added in turn. The resultantmixture was stirred and heated to 100° C. for 4 hours. The mixture wasevaporated and the residue was partitioned between ethyl acetate and a5% aqueous citric acid solution. The organic phase was washed in turnwith water, a saturated aqueous sodium bicarbonate solution and asaturated brine solution, dried over magnesium sulphate and evaporated.The residue was purified by column chromatography on silica using a 9:1mixture of petroleum ether (b.p. 40–60° C.) and ethyl acetate as eluent.There was thus obtained tert-butylN-(5-chloro-1,3-benzodioxol-4-yl)carbamate (1.1 g); NMR Spectrum:(DMSOd₆) 1.45 (s, 9H), 6.1 (s, 2H), 6.85 (d, 1H), 6.95 (d, 1H), 8.75 (s,1H).

A mixture of the material so obtained (1.1 g), trifluoroacetic acid (6ml) and methylene chloride (20 ml) was stirred at ambient temperaturefor 3 hours. The solvent was evaporated and the residue was partitionedbetween ethyl acetate and a saturated aqueous sodium bicarbonatesolution. The organic phase was washed with a saturated brine solution,dried over magnesium sulphate and evaporated. There was thus obtained6-chloro-2,3-methylenedioxyaniline (0.642 g); NMR Spectrum: DMSOd₆) 5.15(s, 2H), 6.0 (s, 2H), 6.25 (d, 1H), 6.75 (d, 1H).

6-Chloro-2,3-methylenedioxyaniline was reacted withbenzyltrimethylammonium dichloroiodate in an analogous manner to thatdescribed in the last paragraph of the portion of Example 1 that isconcerned with the preparation of starting materials. There was thusobtained4-(6-chloro-4-iodo-2,3-methylenedioxyanilino)-3-cyano-6,7-dimethoxyquinolinewhich gave the following characterising data; NMR Spectrum: (DMSOd₆)6.04 (s, 2H), 7.0 (s, 1H).

EXAMPLE 33-cyano-7-ethoxy-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinolinemonohydrochloride salt

Sodium hexamethyldisilazane (1M solution in THF; 1.17 ml) was added to astirred mixture of 4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyaniline(0.12 g), 4-chloro-3-cyano-7-ethoxy-6-methoxyquinoline (0.146 g) and DMF(8 ml) that had been cooled to 0° C. and the resultant mixture wasallowed to warm to ambient temperature and was stirred for 2 hours. Thereaction mixture was diluted with water and extracted with ethylacetate. The organic phase was washed with water and with a saturatedbrine solution, dried over magnesium sulphate and evaporated. Theresidue was purified by column chromatography on silica increasinglypolar mixtures of methylene chloride and methanol as eluent. Thematerial so obtained was dissolved in the minimum quantity of methylenechloride. The solution was diluted with diethyl ether and a solution ofhydrogen chloride in diethyl ether (1M) was added. The resultant solidwas isolated, washed with diethyl ether and dried. Thereby, the productwas obtained the title compound (0.18 g); NMR Spectrum: (DMSOd₆) 1.44(t, 3H), 3.33 (s, 3H), 4.0 (s, 3H), 4.24 (q, 2H), 4.36 (s, 2H), 6.12 (s,2H), 6.96 (d, 1H), 7.03 (d, 1H), 7.45 (s, 1H), 8.11 (s, 1H), 8.96 (s,1H); Mass Spectrum: M+H⁺ 432.

The 4-chloro-3-cyano-7-ethoxy-6-methoxyquinoline used as a startingmaterial was prepared as follows:

Diethyl azodicarboxylate (2.6 g) was added dropwise to a suspension of4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline (1.5 g; prepared asdescribed in International Patent Application WO 00/68201, disclosed ascompound (7) within Preparation 1 therein), ethanol (0.441 g),triphenylphosphine (2.18 g) and methylene chloride (15 ml) and themixture was stirred at ambient temperature for 16 hours. The resultantmixture was washed with water and with a saturated brine solution. Theorganic phase was dried over magnesium sulphate and evaporated. Theresidue was purified by column chromatography on silica usingincreasingly polar mixtures of methylene chloride and ethyl acetate.There was thus obtained 4-chloro-3-cyano-7-ethoxy-6-methoxyquinoline asa solid (0.225 g); NMR Spectrum: (DMSOd₆ at 100° C.) 1.39–1.48 (m, 3H),4.0 (s, 3H), 4.25–4.35 (m, 2H), 7.46 (s, 1H), 7.5 (s, 1H), 8.89 (s, 1H);Mass Spectrum: M+H⁺ 263.

The 4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyaniline used as astarting material was prepared as follows:

N,N-Diisopropylamine (0.231 g) was added to a stirred mixture of4-iodo-2,3-methylenedioxyaniline (0.3 g), methyl 2-propynyl ether (0.16g), bis(triphenylphosphine)palladium(II) dichloride (0.16 g), cuprousiodide (0.065 g) and ethyl acetate (10 ml) that had-been cooled to −20°C. The resultant mixture was allowed to warm to ambient temperature andwas stirred for 16 hours. The reaction mixture was partitioned betweenethyl acetate and a saturated aqueous sodium bicarbonate solution. Theorganic layer was washed with water and with a saturated brine solution,dried over magnesium sulphate and evaporated. The residue was purifiedby column chromatography on silica using increasingly polar mixtures ofisohexane and methylene chloride as eluent. There was thus obtained4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyaniline as a gum (0.2 g); NMRSpectrum: (DMSOd₆) 3.28 (s, 3H), 4.25 (s, 2H), 5.29 (s, 2H), 5.94 (s,2H), 6.2 (d, 1H), 6.64 (d, 1H).

EXAMPLE 43-cyano-6,7-dimethoxy-4-{4-[3-(1,1-dioxotetrahydro-4H-thiazin-4-yl)prop-1-ynyl]-2,3-methylenedioxyanilino}quinoline

N,N-Diisopropylamine (0.043 g) was added to a stirred mixture of3-cyano-4-(4-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinoline (0.2g), 4-(2-propynyl)-1,1-dioxotetrahydro-4H-thiazine (0.145 g),bis(triphenylphosphine)palladium(II) dichloride (0.071 g), cuprousiodide (0.024 g) and ethyl acetate (10 ml) that had been cooled to −20°C. The resultant mixture was allowed to warm to ambient temperature andwas stirred for 16 hours. The reaction mixture was partitioned betweenethyl acetate and a saturated aqueous sodium bicarbonate solution. Theorganic layer was washed with water and with a saturated brine solution,dried over magnesium sulphate and evaporated. The residue was trituratedunder a mixture of acetonitrile and water. The resultant solid wasisolated and dried. There was thus obtained the title compound as asolid (0.05 g); NMR Spectrum: (DMSOd₆) 2.97–3.04 (m, 4H), 3.12–3.18 (m,4H), 3.72 (s, 2H), 3.83 (s, 3), 3.85 (s, 3H), 6.04 (s, 2H), 6.82 (d,1H), 6.95 (d, 1H), 7.31 (s, 1H), 7.74 (s, 1H), 8.48 (s, 1H), 9.6 (s,1H); Mass Spectrum: M+H⁺ 521.

EXAMPLE 53-cyano-6,7-dimethoxy-4-[2,3-methylenedioxy-4(3-morpholinoprop-1-ynyl)anilino]quinolinedihydrochloride salt

Using an analogous procedure to that described in Example4,3-cyano-4(4-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinoline wasreacted with 4-(2-propynyl)morpholine. The reaction mixture waspartitioned between ethyl acetate and a saturated aqueous sodiumbicarbonate solution. The organic layer was washed with water and with asaturated brine solution, dried over magnesium sulphate and evaporated.The residue was purified by column chromatography on silica usingincreasingly polar mixtures of methylene chloride and methanol aseluent. The material so obtained was dissolved in the minimum quantityof methylene chloride. The solution was diluted with diethyl ether and asolution of hydrogen chloride in diethyl ether (1M) was added. Theresultant solid was isolated, washed with diethyl ether and dried. Therewas thus obtained the title compound as a solid (0.065 g); NMR Spectrum:(DMSOd₆ and CD₃CO₂D) 3.24–3.29 (m, 4H), 3.9–3.95 (m, 4H), 4.0 (s, 3H),4.01 (s, 3H), 4.28 (s, 2H), 6.1 (s, 2H); 6.95 (d, 1H), 7.05 (d, 1H),7.49 (s, 1H), 7.5–7.65 (m, 1H), 8.06 (s, 1H), 8.67 (s, 1H); MassSpectrum: M−H⁻ 471.

EXAMPLE 63-cyano-6,7-dimethoxy-4-[2,3-methylenedioxy-4-(3-piperazin-1-ylprop-1-ynyl)anilino]quinolinedihydrochloride salt

Using an analogous procedure to that described in Example1,3-cyano-4-(4-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinolinewas reacted with 1-(2-propynyl)piperazine (J. Med. Chem., 1993, 3,610–616). The reaction mixture was partitioned between methylenechloride and a 2N aqueous hydrochloric acid solution. The organic layerwas dried over magnesium sulphate and evaporated and the residue waspurified by column chromatography on silica using increasingly polarmixtures of methylene chloride and a saturated methanolic ammoniasolution as eluent. The material so obtained was dissolved in theminimum quantity of methylene chloride. The solution was diluted withdiethyl ether and a solution of hydrogen chloride in diethyl ether (1M)was added. The resultant solid was isolated, washed with diethyl etherand dried. There was thus obtained the title compound; NMR Spectrum:(DMSOd₆ and CD₃CO₂D) 3.28–3.44 (m, 8H), 3.99 (s, 3H), 4.0 (s, 3H), 4.27(br s, 2H), 6.15 (s, 2H), 7.04 (d, 1H), 7.14 (d, 1H), 7.5 (s, 1H), 8.24(s, 1H), 9.05 (s, 1H); Mass Spectrum: M−H⁻ 470.

EXAMPLE 74-[4-(5-chloropent-1-ynyl)-2,3-methylenedioxyanilino]-3-cyano-6,7-dimethoxyquinoline

Using an analogous procedure to that described in Example4,3-cyano-4-(4-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinolinewas reacted with 5-chloropent-1-yne. The reaction mixture waspartitioned between ethyl acetate and a saturated aqueous sodiumbicarbonate solution. The organic layer was washed with water and with asaturated brine solution, dried over magnesium sulphate and evaporated.The residue was purified by column chromatography on silica usingincreasingly polar mixtures of methylene chloride and ethyl acetate aseluent. There was thus obtained the title compound as a gum in 69%yield; Mass Spectrum: M+H⁺ 450.

EXAMPLE 83-cyano-6,7-dimethoxy-4-[2,3-methylenedioxy-4-(5-morpholinopent-1-ynyl)anilino]quinolinedihydrochloride salt

Morpholine (5 ml) was added to a mixture of4-[4-(5-chloropent-1-ynyl)-2,3-methylenedioxyalnilino]-3-cyano-6,7-dimethoxyquinoline(0.11 g) and sodium iodide (0.073 g) and the reaction mixture wasstirred at ambient temperature for 16 hours. The resultant mixture wasevaporated and the residue partitioned between methylene chloride andwater. The organic phase was washed with water and with a saturatedbrine solution, dried over magnesium sulphate and evaporated. Theresidue was purified by column chromatography on silica usingincreasingly polar mixtures of methylene chloride and a saturatedmethanolic ammonia solution as eluent. The material so obtained wasdissolved in the minimum quantity of methylene chloride. The solutionwas diluted with diethyl ether and a solution of hydrogen chloride indiethyl ether (1M) was added. The resultant solid was isolated, washedwith diethyl ether and dried. There was thus obtained the title compoundas a solid (0.105 g); NMR Spectrum: (DMSOd₆ and CD₃CO₂D) 1.98–2.04 (m,2H), 2.56–2.65 (m, 2H), 3.04–3.16 (m, 2H), 3.17–3.26 (m, 2H), 3.39–3.51(m, 2H), 3.69–4.02 (m, 10H), 6.06 (s, 2H), 6.9 (d, 1H), 6.98 (d, 1H),7.37 (s, 1H), 7.95 (s, 1H), 8.75 (s, 1H); Mass Spectrum: M+H⁺ 501.

EXAMPLE 9

Using an analogous procedure to that described in Example 3, theappropriate 4-chloro-3-cyanoquinoline was reacted with the appropriate2,3-methylenedioxyaniline to give the compounds described in Table I.Unless otherwise stated, each compound described in Table I was obtainedas a dihydrochloride salt.

TABLE I

Compound No. & Note R¹ (R³)_(n) [1] 3-(4-methylpiperazin-1-yl)propoxy4-(3-methoxyprop-1-ynyl) [2] 3-morpholinopropoxy4-(3-methoxyprop-1-ynyl) [3] 3-morpholinopropoxy6-chloro-4-(3-methoxyprop-1-ynyl) [4]3-(1,1-dioxotetrahydro-4H-thiazin-4- 4-(3-methoxyprop-1-ynyl) yl)propoxy[5] 2-fluoroethoxy 4-(3-methoxyprop-1-ynyl) [6]3-(3-oxopiperazin-1-yl)propoxy 4-(3-methoxyprop-1-ynyl) [7]3-(3-oxopiperazin-1-yl)propoxy 6-chloro-4-(3-methoxyprop-1-ynyl) [8]2-(2-rnethoxyethoxy)ethoxy 4-(3-methoxyprop-1-ynyl) [9] 3-chloropropoxy4-(3-methoxyprop-1-ynyl) [10] 2-(2-chloroethoxy)ethoxy4-(3-methoxyprop-1-ynyl) Notes [1] The product was obtained as atrihydrochloride salt and gave the following characterising data; NMRSpectrum: (DMSOd₆) 2.27–2.38(m, 2H), 2.83(s, 3H), 3.23–3.85(m, 10H),3.34(s, 3H), 4.01(s, 3H), 4.3(t, 2H), 4.35(s, 2H), 6.11(s, 2H), 6.97(d,1H), 7.01(d, 1H), 7.53(s, 1H), 8.21(s, 1H), 8.94(s, 1H); Mass Spectrum:M − H⁻ 542. The4-chloro-3-cyano-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolineused as a starting material was prepared as follows: A mixture of3-bromopropanol (20 ml), N-methylpiperazine (29 ml), potassium carbonate(83 g) and ethanol (200 ml) was stirred and heated to reflux for 20hours. The mixture was cooled to ambient temperature and filtered. Thefiltrate was evaporated and the residue was triturated under diethylether. The resultant mixture was filtered and the filtrate wasevaporated. The residue was purified by distillation at about 60–70° C.under about 0.2 mm Hg to give 1-(3-hydroxypropyl)-4-methylpiperazine (17g); NMR Spectrum: (CDCl₃) 1.72(m, 2H), 2.3(s, 3H), 2.2–2.8(m, 8H),2.6(t, 2H), 3.8(t, 2H), 5.3(br s, 1H). A solution of diisopropylazodicarboxylate (12.1 ml) in methylene chloride (50 ml) was addeddropwise during 30 minutes to a stirred mixture of4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline (12 g),1-(3-hydroxypropyl)-4-methylpiperazine (9.7 g), triphenylphosphine (16.1g) and methylene chloride (200 ml) that had been cooled to 5° C. Theresultant mixture was allowed to warm to ambient temperature and wasthen stirred for 1 hour. Further portions of diisopropylazodicarboxylate (1.2 ml) and triphenylphosphine (1.6 g) were added andthe mixture was stirred at ambient temperature for a further 1 hour. Themixture was poured into water and the organic layer was separated,washed with a saturated brine solution, dried over magnesium sulphateand evaporated. The material so obtained, was purified by columnchromatography on silica using increasingly polar mixtures of methylenechloride and methanol as eluent. There was thus obtained the requiredstarting material as a solid (14.5 g); NMR Spectrum: (DMSOd₆) 1.95(m,2H), 2.13(s, 3H), 2.24–2.5 (m, 10H), 4.0(s, 3H), 4.25(t, 2H), 7.43(s,1H), 7.51(s, 1H), 8.95(s, 1H); Mass Spectrum: M + H⁺ 375 and 377. [2]4-Chloro-3-cyano-6-methoxy-7-(3-morpholinopropoxy)quinoline(International Patent Application WO 00/68201, page 52) was used as astarting material. The product gave the following characterising data;NMR Spectrum: (DMSOd₆) 2.3–2.38(m, 2H), 3.04–3.14(m, 2H), 3.25–3.31(m,2H), 3.35(s, 3H), 3.44–3.52(m, 2H), 3.78–3.86(m, 2H), 3.98(d, 2H),4.01,(s, 3H), 4.3(t, 2H), 4.36(s, 2H), 6.14(s, 2H), 7.0(d, 1H), 7.03(d,1H), 7.55(s, 1H), 8.21(s, 1H), 8.94(s, 1H); Mass Spectrum: M + H⁺ 531.[3] The product gave the following characterising data; NMR Spectrum:(DMSOd₆) 2.26–2.35(m, 2H), 3.03–3.14(m, 2H), 3.22–3.31(m, 2H), 3.33(s,3H), 3.44–3.51(m, 2H), 3.81(t, 2H), 3.91–4.0(m, 5H), 4.3.(t, 2H),4.36(s, 2H), 6.2(d, 2H), 7.22(s, 1H), 7.51(s, 1H), 8.15(s, 1H), 8.86(s,1H); Mass Spectrum: M −H⁻ 563 and 565. The6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyaniline used as astarting material was prepared as follows: N,N-Diisopropylamine (0.68 g)was added to a stirred mixture of6-chloro-4-iodo-2,3-methylenedioxyaniline (1 g), methyl 2-propynyl ether(0.471 g), bis(triphenylphosphine)palladium (II) dichloride (0.472 g),cuprous iodide (0.192 g) and ethyl acetate (20 ml) that had been cooledto −20° C.. The resultant mixture was allowed to warm to ambienttemperature and was stirred for 16 hours. The reaction mixture waspartitioned between ethyl acetate and a saturated aqueous sodiumbicarbonate solution. The organic layer was washed with water and with asaturated brine solution, dried over magnesium sulphate and evaporated.The residue was purified by column chromatography on silica usingincreasingly polar mixtures of isohexane and methylene chloride aseluent. There was thus obtained6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyaniline as a solid(0.2 g); NMR Spectrum: (DMSOd₆) 3.28(s, 3H), 4.26(s, 2H), 5.52(s, 2H),6.05(s, 2H), 6.93(s, 1H). [4] The product gave the followingcharacterising data; NMR Spectrum: (DMSOd₆) 2.2–2.27(m, 2H), 3.16–3.2(m,2H), 3.36(s, 3H), 3.37–3.54(m, 8H), 4.0(s, 3H), 4.3–4.37(m, 4H), 6.19(s,2H), 6.8(d, 1H), 7.0(d, 1H), 7.46(s, 1H), 8.0(s, 1H), 8.74(s, 1H); MassSpectrum: M − H⁻ 577. The4-chloro-3-cyano-7-[3-(1,1-dioxotetrahydro-4H-thiazin-4-yl)propoxy]-6-methoxyquinolineused as a starting material was prepared as follows: A mixture of3-aminopropan-1-ol (0.65 ml) and divinyl sulphone (1 g) was heated to110° C. for 45 minutes. The mixture was allowed to cool to ambienttemperature and was purified by column chromatography on silica using a19:1 mixture of inethylene chloride and methanol as eluent. There wasthus obtained 4-(3-hydroxypropyl)-1,1-dioxotetrahydro-4H-thiazine (0.8g); NMR Spectrum: (CDCl₃) 1.7–1.8(m, 2H), 2.73(t, 2H), 3.06(br s, 8H),3.25(s, 1H), 3.78(t, 2H); Mass Spectrum: M + H⁺ 194. Diethylazodicarboxylate (1.72 g) was added dropwise to a suspension of4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline (1 g),4-(3-hydroxypropyl)-1,1-dioxotetrahydro-4H-thiazine (1.23 g),triphenylphosphine (1.45 g) and methylene chloride (10 ml) and themixture was stirred at ambient temperature for 16 hours. The resultantmixture was washed with water and with a saturated brine solution. Theorganic phase was dried over magnesium sulphate and evaporated. Theresidue was purified by column chromatography on silica usingincreasingly polar mixtures of methylene chloride, ethyl acetate and asaturated methanolic ammonia solution as eluent. The material soobtained was triturated under diethyl ether. There was thus obtained4-chloro-3-cyano-7-[3-(1,1-dioxotetrahydro-4H-thiazin-4-yl)propoxy]-6-methoxyquinoline(0.15 g); NMR Spectrum: (DMSOd₆) 1.96(m, 2H), 2.64 (t, 2H), 2.88–2.93(m,4H), 3.07–3.12(m, 4H), 4.0(s, 3H), 4.29(t, 2H), 7.44(s,1H), 7.55(s, 1H),8.96(s, 1H); Mass Spectrum: M + H⁺ 410. [5] The product was obtained asa monohydrochloride salt and gave the following characterising data; NMRSpectrum: (DMSOd₆) 3.33(s, 3H), 4.0(s, 3H), 4.35(s, 2H), 4.39–4.43(m,1H), 4.49–4.53(m, 1H), 4.75–4.8(m, 1H), 4.91–4.96(m, 1H), 6.12(s, 2H),6.96(d, 1H), 7.01(d, 1H), 7:48(s, 1H), 8.13(s, 1H), 8.94(s, 1H); MassSpectrum: M + H⁺ 450. The4-chloro-3-cyano-7-(2-fluoroethoxy)-6-methoxyquinoline used as astarting material was prepared by the reaction of4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline and 2-fluoroethanol usingan analogous procedure to that described in Note [4] immediately aboveexcept that the residue was purified by column chromatography on silicausing increasingly polar mixtures of methylene chloride and ethylacetate as eluent. The material so obtained gave the followingcharacterising data; NMR Spectrum: (DMSOd₆) 4.0l (s, 3H), 4.43–4.48(m,1H), 4.53–4.58(m, 1H), 4.74–4.78(m, 1H), 4.9–4.94(m, 1H), 7.42(s, 1H),7.56(s, 1H), 8.96(s, 1H); Mass Spectrum: M + H⁺ 281. [6] The product wasobtained as a free base after chromatographic purification and was notconverted into a hydrochloride salt. The product gave the followingcharacterising data; NMR Spectrum: (DMSOd₆ and CD₃CO₂D) 1.96–2.02(m,2H), 2.6–2.68(m, 4H), 3.03(s, 2H), 3.21(m, 2H), 3.34(s, 3H), 3.94(s,3H), 4.21(t, 2H), 4.3(s, 2H), 6.01(s, 2H), 6.76(d, 1H), 6.91(d, 1H),7.34(s, 1H), 7.71(s, 1H), 8.41(s, 1H); Mass Spectrum: M − H⁻ 542. The4-chloro-3-cyano-6-methoxy-7-[3-(3-oxopiperazin-1-yl)propoxy]quinolineused as a starting material was prepared by the reaction of4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline and4-(3-hydroxypropyl)piperazin-2-one (Tet. Letters, 1994, 35, 9545) usingan analogous procedure to that described in Note [4] immediately above.The material so obtained gave the following characterising data; NMRSpectrum: (DMSOd₆) 1.92–2.03(m, 2H), 2.49–2.59(m, 4H), 2.94(s, 2H),3.1–3.17(m, 2H), 4.0(s, 3H), 4.27(t, 2H), 7.42(s, 1H), 7.51(s, 1H),7.69(s, 1H), 8.95(s, 1H); Mass Spectrum: M + H⁺ 375. [7] The productgave the following characterising data; NMR Spectrum: (DMSOd₆)2.29–2.36(m, 2H), 3.21–3.41(m, 5H), 3.55–3.9(m, 4H), 3.99(s, 3H),4.28–4.32(m, 2H), 4.35(s, 2H), 5.99(s, 1H), 6.01(s, 1H), 6.01(s, 2H),7.21(s, 1H), 7.48(s, 1H), 8.11(s, 1H), 8.81(s, 1H); Mass Spectrum: M +H⁺ 578 and 580. [8] The product was obtained as a monohydrochloride saltand gave the following characterising data; NMR Spectrum: (DMSOd₆ andCD₃CO₂D) 3.26(s, 3H), 3.36(s, 3H), 3.49(t, 2H), 3.54(t, 2H), 3.86(t,2H), 4.0(s, 3H), 4.32–4.36(m, 4H), 6.09(s, 2H), 6.91(d, 1H), 7.0(d, 1H),7.48(s, 1H), 8.01(s, 1H), 8.75(s, 1H); Mass Spectrum: M + H⁺ 506. The4-chloro-3-cyano-6-methoxy-7-[2-(2-methoxyethoxy)ethoxy]quinoline usedas a starting material was prepared by the reaction of4-chloro-3-cyano-7-hyroxy-6-methoxyquinoline and2-(2-methoxyethoxy)ethanol using an analogous procedure to thatdescribed in Note [4] immediately above except that the residue waspurified by column chromatography on silica using increasingly polarmixtures of methylene chloride and ethyl acetate as eluent. The materialso obtained gave the following characterising data; NMR Spectrum:(DMSOd₆) 3.23(s, 3H), 3.46(m, 2H), 3.61(m, 2H), 3.82(m, 2H), 4.0(s, 3H),4.34(t, 2H), 7.42(s, 1H), 7.55(s, 1H), 8.95(s, 1H). [9] The product wasobtained as a free base after chromatographic purification and was notconverted into a hydrochloride salt. The product gave the followingcharacterising data; NMR Spectrum: (DMSOd₆) 2.25(m, 2H), 3.32(s, 3H),3.8(t, 2H), 3.92(s, 3H), 4.27(t, 2H), 4.34(s, 2H), 6.05(s, 2H), 6.82(d,1H), 6.96(d, 1H), 7.35(s, 1H), 7.74(s, 1H), 8.47(s, 1H), 9.60(s, 1H);Mass Spectrum: M + H⁺ 480. The4-chloro-7-(3-chloropropoxy)-3-cyano-6-methoxyquinoline used as astarting material was prepared as follows: A mixture of4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline (0.2 g), potassiumtert-butoxide (0.1 g) and DMF(8 ml) was stirred at ambient temperaturefor 15 minutes. 1-Bromo-3-choropropane (0.134 g) was added and thereaction mixture was stirred at ambient temperature for 16 hours. Theresultant mixture was evaporated and the residue was partitioned betweenmethylene chloride and an aqueous sodium bicarbonate solution. Theorganic layer was dried using magnesium sulphate and evaporated. Theresidue was purified by column chromatography on silica usingincreasingly polar mixtures of ethyl acetate and hexane. There was thusobtained the required starting material (0.131 g); NMR Spectrum:(DMSOd₆) 2.3(m, 2H), 3.8(m, 2H), 4.0(s, 3H), 4.35(m, 2H), 7.42(s, 1H),7.68(s, 1H), 8.95(s, 1H); Mass Spectrum: M + H⁺ 311. [10] The productwas obtained as a free base after chromatographic purification and wasnot converted into a hydrochloride salt. The product gave the followingcharacterising data; NMR Spectrum: (DMSOd₆) 3.32(s, 3H), 3.72–3.78(m,4H), 3.85–3.89(m, 2H), 3.91(s, 3H), 4.28(t, 2H), 4.34(s, 2H), 6.05(s,2H), 6.82(d, 1H), 6.95(d, 1H), 7.35(s, 1H), 7.74(s, 1H), 8.47(s, 1H),9.60(s, 1H); Mass Spectrum: M + H⁺ 510. The4-chloro-7-[2-(2-chloroethoxy)ethoxy]-3-cyano-6-methoxyquinoline used asa starting material was prepared by the reaction of4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline and2-(2-chloroethoxy)ethanol using an analogous procedure to that describedin Note [4] immediately above except that the residue was purified bycolumn chromatography on silica using increasingly polar mixtures ofmethylene chloride and ethyl acetate as eluent. The material so obtainedgave the following characterising data; NMR Spectrum: (DMSOd₆)3.72–3.8(m, 4H), 3.88–3.93(m, 2H), 4.0(s, 3H), 4.33–4.39(m, 2H), 7.4(s,1H), 7.55(s, 1H), 8.94(s, 1H); Mass Spectrum: M + H⁺ 341.

EXAMPLE 103-cyano-7-{3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy}-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinolinedihydrochloride salt

A mixture of7-(3-chloropropoxy)-3-cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline(0.14 g), 1-(2-fluoroethyl)piperazine trifluoroacetic acid salt (0.158g), diisopropylethylamine (0.189 g), sodium iodide (0.02 g) and2-methoxyethanol (20 ml) was stirred and heated to 100° C. for 30 hours.The cooled mixture was evaporated and the resultant residue waspartitioned between ethyl acetate and water. The organic layer was driedover magnesium sulphate and evaporated and the residue was purified bycolumn chromatography on silica using increasingly polar mixtures ofmethylene chloride and methanol as eluent. The material so obtained wasdissolved in the minimum quantity of methylene chloride. The solutionwas diluted with diethyl ether and a solution of hydrogen chloride indiethyl ether (1M) was added. The resultant solid was isolated, washedwith diethyl ether and dried. There was thus obtained the title compound(0.045 g); NMR Spectrum: (DMSOd₆ and CF₃CO₂D at 100° C.) 2.22–2.31 (m,2H), 2.98–3.1 (m, 6H), 3.1.6–3.21 (m, 2H), 3.25–3.31 (m, 4H), 3.36 (s,3H), 3.99 (s, 3H), 4.3–4.34 (m, 4H), 4.6 (t, 1H), 4.72 (t, 1H), 6.08 (s,2H), 6.9 (d, 1H), 6.98 (d, 1H), 7.49 (s, 1H), 7.96 (s, 1H), 8.69 (s,1H); Mass Spectrum: M+H⁺ 576.

The 1-(2-fluoroethyl)piperazine trifluoroacetic acid used as a startingmaterial was prepared as follows:

A mixture of 1-(tert-butoxycarbonyl)piperazine (5 g),1-bromo-2-fluoroethane (5.11 g), potassium carbonate (9.26 g) andacetonitrile (60 ml) was stirred and heated to 60° C. for 4 hours. Thereaction mixture was cooled to ambient temperature and filtered and thefiltrate was evaporated. The residue was purified by columnchomatography on silica using increasingly polar mixtures of isohexaneand ethyl acetate as eluent. There was thus obtained4-(tert-butoxycarbonyl)-1-(2-fluoroethyl)piperazine as a solid (3.7 g);NMR Spectrum: (DMSOd₆ and CD₃CO₂D) 1.37 (s, 9H), 2.34–2.4 (m, 4H), 2.56(t, 1H), 2.67 (t, 1H), 3.25–3.34 (m, 4H), 4.42 (t, 1H), 4.58 (t, 1H).

Trifluoroacetic acid (20 ml) was added to a mixture of4-(tert-butoxycarbonyl)-1-(2-fluoroethyl)piperazine (3.7 g),triethylsilane (8 ml) and methylene chloride (100 ml) and the resultantmixture was stirred at ambient temperature for 1.5 hours. The mixturewas evaporated and the residue was triturated under diethyl ether. Thesolid so obtained was isolated, washed with diethyl ether and dried.There was thus obtained 1-(2-fluoroethyl)piperazine trifluoroacetic acidsalt as a solid (6.0 g); NMR Spectrum: DMSOd₆ and CD₃CO₂D) 3.0–3.31 (m,10H), 4.59 (m, 1H), 4.75 (m, 1H).

EXAMPLE 117-[3-(4-acetylpiperazin-1-yl)propoxy]-3-cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinolinedihydrochloride salt

Using an analogous procedure to that described in Example 10,7-(3-chloropropoxy)-3-cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinolinewas reacted with 1-acetylpiperazine to give the title compound in 58%yield; NMR Spectrum: (DMSOd₆ and CF₃CO₂D at 100° C.) 2.04 (s, 3H),2.3–2.37 (m, 2H), 3.27–3.37 (m, 9H), 3.74–3.84 (m, 4H), 3.96 (s, 3H),4.3–4.36 (m, 4H), 6.04 (s, 2H), 6.89 (d, 1H), 6.96 (d, 1H), 7.51 (s,1H), 7.96 (s, 1H), 8.66 (s, 1H); Mass Spectrum: M+H⁺ 572.

EXAMPLE 123-cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]-7-[2-(2-pyrrolidin-1-ylethoxy)ethoxy]quinolinedihydrochloride salt

Pyrrolidine (10 ml) was added to a mixture of7-[2-(2-chloroethoxy)ethoxy]-3-cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline(0.225 g) and sodium iodide (0.133 g) and the reaction mixture wasstirred at ambient temperature for 24 hours. The reaction mixture wasevaporated and the residue was triturated under methylene chloride. Theresultant solid was washed with water and dried. The material soobtained was dissolved in the minimum quantity of ethyl acetate and asolution of hydrogen chloride in diethyl ether (1M) was added. Theresultant solid was isolated, washed with diethyl ether and dried. Therewas thus obtained the title compound as a solid (0.145 g); NMR Spectrum:(DMSOd₆ and CD₃CO₂D at 100° C.) 1.84–1.89 (m, 4H), 3.29–3.39 (m, 9H),3.88 (m, 2H), 3.94 (m, 2H), 3.96 (s, 3H), 4.3 (s, 2H), 4.36 (m, 2H),6.04 (s, 2H), 6.84 (d, 1H), 6.94 (d, 1H), 7.46 (s, 1H), 7.87 (s, 1H),8.56 (s, 1H); Mass Spectrum: M+H⁺ 545.

EXAMPLE 133-[4-(3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylenedioxyphenyl]acrylonitrile

A mixture of3-cyano-4-(4-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinoline (0.2g), acrylonitrile (0.2 ml), triethylamine (0.2 ml), palladium(II)acetate (0.01 g) and DMF (2 ml) was stirred and heated to 115° C. for 3hours. The reaction mixture was evaporated and the residue was purifiedby column chromatography on silica using increasingly polar mixtures ofhexane and ethyl acetate as eluent. The material so obtained wastriturated under diethyl ether. There was thus obtained the titlecompound, in the form of a 4:1 mixture of trans and cis isomers and as ayellow solid (0.095 g); NMR Spectrum: (DMSOd₆, data relating to themajor trans isomer) 3.91 (s, 3H), 3.93 (s, 3H), 6.12 (s, 2H), 6.26 (d,1H), 6.88 (d, 1H), 7.14 (d, 1H), 7.35 (s, 1H), 7.56 (d, 1H), 7.7 (s,1H), 8.51 (s, 1H), 9.7 (s, 1H); Mass Spectrum: M+H⁺ 401.

EXAMPLE 14

Using an analogous procedure to that described in Example 13, theappropriate4-(4-iodo-2,3-methylenedioxyanilino)-3-cyano-6,7-(dimethoxyquinoline wasreacted with the appropriate olefin to give the compounds described inTable II.

TABLE II

Compound No. & Note R¹ (R³)_(n) [1] methoxy 6-chloro-4-(2-cyanovinyl)[2] methoxy 4-(2-methoxycarbonylvinyl) [3] methoxy6-chloro-4-(2-methoxycarbonylvinyl) [4] methoxy 4-(2-propionylvinyl) [1]The required olefin was acrylonitrile. The product was obtained as thetrans isomer and gave the following characterising data; NMR Spectrum:(DMSOd₆) 3.94(s, 3H), 3.98(s, 3H), 6.17(s, 2H), 6.32(d, 1H), 7.33(s,1H), 7.36(s, 1H), 7.49(d, 1H), 7.84(s, 1H), 8.39(s, 1H), 9.6(br s, 1H);Mass Spectrum: M + H⁺ 435 and 437. [2] The required olefin was methylacrylate. The product was obtained as the trans isomer and gave thefollowing characterising data; NMR Spectrum: (DMSOd₆) 3.72(s, 3H),3.91(s, 3H), 3.93(s, 3H), 6.12(s, 2H), 6.29(d, 1H), 6.88(d, 1H), 7.22(d,1H), 7.35(s, 1H), 7.59(d, 1H), 7.74(s, 1H), 8.51(s, 1H), 9.68(s, 1H);Mass Spectrum: M + H⁺ 434. [3] The required olefin was methyl acrylate.The reaction solvent was a 6:1 mixture of acetonitrile and DMF and thereaction mixture was heated to 80° C. for 5 hours. The product wasobtained as the trans isomer and gave the following characterising data;NMR Spectrum: (DMSOd₆) 3.74(s, 3H), 3.95(s, 6H), 6.22(d, 2H), 6.7(d,1H), 7.33(s, 1H), 7.53(s, 1H), 7.59(d, 1H), 7.86(s, 1H), 8.44(s, 1H),9.45(s, 1H); Mass Spectrum: M + H⁺ 468 and 470. [41 The required olefmwas ethyl vinyl ketone. The product was obtained as the trans isomer andgave the following characterising data; NMR Spectrum: (DMSOd₆) 1.03(t,3H), 2.70(q, 2H), 3.91(s, 3H), 3.93(s, 3H), 6.12(s, 2H), 6.83–6.93(m,2H), 7.22(d, 1H), 7.35(s, 1H), 7.52(d, 1H), 7.74(s, 1H), 8.51(s, 1H),9.65(s, 1H); Mass Spectrum: M + H⁺ 432.

EXAMPLE 15(2E)-3-[4-(3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylenedioxyphenyl]acrylicacid

A mixture of methyl(2E)-3-[4(3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylenedioxyphenyl]acrylate(0.75 g), a 1N aqueous sodium hydroxide solution (12 ml) and methanol(45 ml) was stirred and warmed to 40° C. for 12 hours. The reactionmixture was evaporated. Water was added and the mixture was acidified bythe addition of 2N aqueous hydrochloric acid solution. The resultantprecipitate was isolated and dried. There was thus obtained the titlecompound as a solid (0.703 g); NMR Spectrum: (DMSOd₆) 3.98 (s, 6H), 6.19(s, 2H), 6.59 (d, 1H), 7.02 (d, 1H), 7.28 (d, 1H), 7.48 (s, 1H), 7.55(d, 1H), 8.09 (s, 1H), 8.95 (s, 1H); Mass Spectrum: M+H⁺ 420.

EXAMPLE 16N-{(2E)-3-[4-(3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylenedioxyphenyl]acryloyl}morpholine

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.196 g)was added to a mixture of(2E)-3-[4-(3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylenedioxyphenyl]acrylicacid (0.35 g), morpholine (0.36 ml), N-methylmorpholine (0.112 ml),1-hydroxybenzotriazole (0.112 ml), DMF (2 ml) and methylene chloride (10ml) and the reaction mixture was stirred at ambient temperature for 12hours. The resultant mixture was partitioned between methylene chlorideand water. The organic layer was dried over magnesium sulphate andevaporated and the residue was purified by column chromatography onsilica using increasingly polar mixtures of methylene chloride andmethanol as eluent. The material so obtained was triturated underdiethyl ether. There was thus obtained the title compound as a solid(0.031 g); NMR Spectrum: (DMSOd₆) 3.66 (s, 8H), 3.96 (s, 6H), 6.09 (s,2H), 6.87 (d, 1H), 7.19 (d, 1H), 7.28 (d, 1H), 7.34 (s, 1H), 7.49 (d,1H), 7.77 (s, 1H), 8.48 (s, 1H), 9.63 (s, 1H); Mass Spectrum: M+H⁺ 489.

EXAMPLE 17(2E)-3-[4-(3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylenedioxyphenyl]-N-(2-methoxyethyl)acrylamide

Using an analogous procedure to that described in Example 16,(2E)-3-[4-(3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylenedioxyphenyl]acrylicacid was reacted with 2-methoxyethylamine to give the title compound in64% yield; NMR Spectrum: (DMSOd₆) 3.22–3.43 (m, 7H), 3.95 (s, 3H), 3.96(s, 3H), 6.1 (s, 2H), 6.74 (d, 1H), 6.87 (d, 1H), 7.07 (d, 1H), 7.32 (s,2H), 7.73 (s, 1H), 8.22 (t, 1H), 8.48 (s, 1H), 9.62 (s, 1H); MassSpectrum: M+H⁺ 477.

EXAMPLE 18(2E)-3-[4-(3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylenedioxyphenyl]-N-(2-methoxyethyl)-N-methylacrylamide

Using an analogous procedure to that described in Example 16,(2E)-3-[4-(3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylenedioxyphenyl]acrylicacid was reacted with N-(2-methoxyethyl)-N-methylamine to give the titlecompound in 47% yield; NMR Spectrum: (DMSOd₆) 2.94 (s, 1.5H), 3.08 (s,1.5H), 3.17 (s, 3H), 3.43–3.65 (m, 4H), 3.95 (s, 3H), 3.96 (s, 3H), 6.1(s, 2H), 6.84 (d, 1H), 7.16 (d, 1H), 7.25 (d, 1H), 7.33 (s, 1H), 7.43(d, 1H), 7.76 (s, 1H), 8.48 (s, 1H), 9.62 (s, 1H); Mass Spectrum: M+H⁺491.

EXAMPLE 193-cyano-6,7-dimethoxy-4-[5-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline

A mixture of4-(5-bromo-2,3-methylenedioxyanilino)-3-cyano-6,7-dimethoxyquinoline(0.15 g), methyl 2-propynyl ether (0.049 g),tetrakis(triphenylphosphine)palladium(0) (0.02 g) and pyrrolidine (2 ml)was stirred and heated to 80° C. for 8 hours. The resultant mixture wascooled to ambient temperature, poured into a dilute aqueous ammoniumchloride solution and extracted with ethyl acetate. The organic phasewas washed with water and with a saturated brine solution, dried overmagnesium sulphate and evaporated. The residue was purified by columnchromatography on silica using increasingly polar mixtures of methylenechloride and methanol as eluent. There was thus obtained the titlecompound as a solid (0.032 g); NMR Spectrum: (CDCl₃) 3.4 (s, 3H), 3.77(s, 3H), 4.04 (s, 3H), 4.24 (s, 2H), 5.97 (s, 2H), 6.65 (br s, 1H), 6.73(d, 1H), 6.78 (d, 1H), 6.99 (s, 1H), 7.38 (s, 1H), 8.63 (s, 1H); MassSpectrum: M+H⁺ 418.

The 4-(5-bromo-2,3-methylenedioxyanilino)-3-cyano-6,7-dimethoxyquinolineused as a starting material was prepared as follows:

A mixture of 6-bromo-1,3-benzodioxole-4-carboxylic acid [Khimn.Geterotsikl. Soedin 1979, 9, 1183–8 (Chemical Abstracts 22, 94280); 0.92g], diphenylphosphoryl azide (1.08 g), tert-butanol (3 ml),triethylamine (0.34 g) and toluene (15 ml) were stirred and heated at100° C. for 4 hours. The resultant mixture was evaporated and theresidue was partitioned between methyl tert-butyl ether and a 5% aqueouscitric acid solution. The organic phase was washed with water and asaturated aqueous sodium bicarbonate solution, dried over magnesiumsulphate and evaporated. The residual oil was purified by columnchromatography on silica using a 5:1 mixture of isohexane and ethylacetate as eluent. There was thus obtained tert-butylN-(6-bromo-1,3-benzodioxol-4-yl)carbamate (0.6 g); NMR Spectrum: (CDCl₃)1.52 (s, 9H), 5.95 (s, 2H), 6.39 (br s, 1H), 6.7 (d, 1H), 7.73 (br s,1H).

A mixture of the material so obtained, trifluoroacetic acid (3 ml) andmethylene chloride (8 ml) was stirred at ambient temperature for 1 hour.The solvent was evaporated and the residue was partitioned betweenmethyl tert-butyl ether and a saturated aqueous sodium bicarbonatesolution. The organic phase was washed with a saturated brine solution,dried over magnesium sulphate and evaporated. The residue was purifiedby column chromatography on silica using a 4:1 mixture of isohexane andethyl acetate as eluent. There was thus obtained5-bromo-2,3-methylenedioxyailine (0.318 g) as a colourless solid; NMRSpectrum: (CDCl₃) 3.6 (br s, 2H), 5.92 (s, 2H), 6.27 (m, 2H).

Using an analogous procedure to that described in Example3,4-chloro-3-cyano-6,7-dimethoxyquinoline (0.65 g) was reacted with5-bromo-2,3-methylenedioxyaniline (0.587 g). The free base obtainedafter chromatographic purification was not converted into thedihydrochloride salt. There was thus obtained4-(5-bromo-2,3-methylenedioxyanilino)-3-cyano-6,7-dimethoxyquinoline asa solid (1.16 g); NMR Spectrum: (CDCl₃) 3.83 (s, 3H), 4.05 (s, 3H), 5.98(s, 2H), 6.76 (d, 1H), 6.84 (d, 1H), 6.9 (br s, 1H), 7.06 (s, 1H), 7.39(s, 1H), 8.64 (s, 1H); Mass Spectrum: M+H⁺ 428 and 430.

EXAMPLE 203-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinolinedihydrochloride salt

A mixture of4-chloro-3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline (165mg) and 4-(3-methoxyprop-1-ynyl)-2,3-methylendioxyaniline (123 mg) in1-propanol (10 ml) was treated with a 1.0M solution of hydrogen chloridein diethyl ether (0.5 ml) then stirred and heated at reflux for 2 hours.On cooling a solid precipitated from the reaction mixture. The resultingsuspension was basified with aqueous ammonia and evaporated to a gum.This residue was purified by multi-injection preparative RP HPLC[Kromasil C18 5 μm silica column, 100 mm×10 mm; eluted with a mixture ofacetonitrile (55%) and 0.1% aqeous ammonia solution (45%)]. Afterisolation, the major product was converted to its dihydrochloride saltin acetonitrile using two equivalents of a 1.0M solution of hydrogenchloride in diethyl ether. The title compound was thus obtained as ayellow solid (81 mg); NMR Spectrum: (DMSOd₆ & CD₃COOD, 373K) 2.17 (m,2H), 2.38 (m, 2H), 2.77 (s, 3H), 3.30 (m, 4H), 3.37 (s, 3H), 3.96 (s,3H), 4.33 (s, 2H), 5.04 (m, 1H), 6.12 (s, 2H), 6.92 (d, 1H), 6.97 (m,2H), 7.08 (s, 1H), 8.63 (s, 1H); Mass Spectrum: M+H⁺ 501.

The 4-(3-methoxyprop-1-ynyl)-2,3-methylendioxyaniline used as a startingmaterial was prepared as described in example 3.

The 4-chloro-3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinolineused as a starting material was prepared as follows:

i) Preparation of ethyl(2-E/Z)-2-cyano-3-[(3,5-difluorophenyl)amino]acrylate

A mixture of 3,5-difluoroaniline (32.25 g) and ethyl2-cyano-3-ethoxyacrylate (42.25 g) dissolved in ethanol (200 ml) wasrefluxed for 2 hours and then allowed to cool. The product was filteredoff and washed with a little ethanol to give the title compound as Whiteneedles (58.0 g; 92%); NMR spectrum: (DMSOd₆) E/Z or Z/E mixture 64/36,1.28 (m, 3H), 4.23 (m, 2H), 6.98–7.42 (m, 3H), 8.44 (m, 1H), 10.80 (m,1H); Mass spectrum: M+H⁺ 253.

ii) Preparation of 3-cyano-5,7-difluoro-4-hydroxyquinoline

Di(ethylene glycol) dibutyl ether (100 ml) was refluxed at 255° C. undernitrogen in a 250 ml flask. To this was added ethyl(2-E/Z)-2-cyano-3-[(3,5-difluorophenyl)amino]acrylate (12.5 g) inportions over 10 minutes. The mixture was heated for a further 30minutes and then allowed to cool. The precipitated solid was collectedand washed with ethyl acetate. The title compound was thus obtained as agrey/brown solid (4.24 g, 41%); NMR spectrum: (DMSOd₆) 7.21 (m, 1H),7.30 (m, 1H), 8.72 (s, 1H), 12.86 (broad, 1H); Mass spectrum: M+H⁺ 207.

iii) Preparation of3-cyano-7-fluoro-4-hydroxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline

A mixture of 3-cyano-5,7-difluoro-4-hydroxyquinoline (4.12 g),1-methylpiperidin-4-ol (2.6 g) and potassium tert-butoxide (6.72 g) inanhydrous tetrahydrofuran (250 ml) was stirred and heated at 60° C. for2 hours. Acetic acid was added until pH6 was reached and then thesolution was evaporated to dryness. The residue was dissolved in amixture of dichloromethane and methanol (2:1) and the solution added topowdered silica gel (15 g). The suspension was evaporated to dryness andpowder was packed into a preload cartridge. This was thenchromatographed with an Isco Combiflash system and a Biotage 40M silicacartridge using a gradient elution of 0.6% to 30% ammonia (7.0M inmethanol) in dichloromethane. The fractions containing the product werecombined and evaporated. This gave the title compound as a white foam(3.55 g, 59%); NMR spectrum: (DMSOd₆) 1.77 (m, 2H), 1.92 (m, 2H), 2.30(s, 3H), 2.43 (m, 2H), 2.81 (m, 2H), 4.55 (m, 1H), 6.81 (m, 2H), 8.40(s, 1H), Mass spectrum: M+H⁺ 302.

iv) Preparation of3-cyano-4-hydroxy-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline

A mixture of3-cyano-7-fluoro-4-hydroxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline (600mg), methanol (0.40 ml) and potassium tert-butoxide (1.0M solution intetrahydrofuran; 10.0 ml) in anhydrous dimethyl sulphoxide (20 ml) washeated at 70° C. for 16 hours. The solution was cooled and then dilutedwith water (100 ml). Dilute hydrochloric acid was added until pH6 wasreached and the by-product precipitate(3-cyano-4-hydroxy-5,7-dimethoxyquinoline) was filtered off. Thefiltrate was pumped onto a cation exchange cartridge (Waters Oasis MCX6.0 g) and washed on with water. The column was flushed successivelywith water (200 ml), methanol/water (1:1; 200 ml) and methanol (200 ml).The product was eluted off the column with methanol containingtriethylamine (1%). The fractions containing the product were combinedand evaporated. This gave the title compound as an white solid (460 mg,73%); NMR spectrum: (DMSOd₆) 1.67 (m, 2H), 1.83 (m, 2H), 2.12 (m, 2H),2.15 (s, 3H), 2.64 (m, 2H), 4.31 (m, 1H), 6.31 (d, 1H), 6.56 (d, 1H),8.16 (s, 1H); Mass spectrum: M+H⁺ 314.

v) Preparation of4-chloro-3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline

A mixture of3-cyano-4-hydroxy-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline(313 mg) and phosphoryl chloride (1.8 ml) in acetonitrile (10 ml) wasrefluxed and stirred for 20 hours. After cooling, the solution wasevaporated to dryness. The flask containing the residue was filled withice chips and excess concentrated aqueous ammonia (25 ml) was added.This mixture was allowed to warm up while stirring overnight. Theproduct was filtered off and dried under high vacuum overnight. Thetitle compound was obtained as a white solid (225 mg, 68%); NMRspectrum: (DMSOd₆) 1.80 (m, 2H), 1.98 (m, 2H), 2.18 (s, 3H), 2.27 (m,2H), 2.58 (m, 2H), 3.94 (s, 3H), 4.72 (m, 1H), 6.92 (d, 1H), 7.09 (d,1H), 8.93 (s, 1H); Mass spectrum: M+H⁺ 332.

EXAMPLE 213-cyano-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinolinedihydrochloride salt

A mixture of4-chloro-3-cyano-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinoline(125 mg) and 4-(3-methoxyprop-1-ynyl)-2,3-methylendioxyaniline (179 mg)in 1-propanol (8 ml) was treated with a 11.0M solution of hydrogenchloride in diethyl ether (0.30 ml) then stirred and heated at refluxfor 1 hour. The mixture was allowed to cool and neutralised by theaddition of tetramethylguanidine (0.10 ml). The resulting solution wasevaporated to dryness and the residue was purified by chromatography ona Biotage silica cartridge (20 g) eluting with a gradient of methanol indichloromethane (1–10%). The fractions containing the product werecombined and evaporated. The residue was dissolved in ethanol (8 ml) andtreated with 2 equivalents of hydrogen chloride (1.0M in diethyl ether).The title compound was thus obtained as a white solid (130 mg); NMRSpectrum: (DMSOd₆, 300K) 1.87 (m, 2H), 2.10 (m, 2H), 2.31 (m, 2H), 3.11(m, 2H), 3.30 (m, 2H), 3.36 (s, 3H), 3.50 (m, 4H), 3.87 (m, 4H), 3.97(m, 2H), 4.32 (m, 2H), 4.37 (s, 2H), 5.10 (m, 1H), 6.18 (s, 2H), 1.05(m, 3H), 7.13 (s, 1H), 8.87 (s, 1H), 10.43 (s, 1H), 11.34 (s, 1H); MassSpectrum: M+H⁺ 601.

The 4-(3-methoxyprop-1-ynyl)-2,3-methylendioxyaniline used as a startingmaterial was prepared as described in example 3.

The4-chloro-3-cyano-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinolineused as a starting material was prepared as follows:

i) 3-cyano-5,7-difluoro-4-hydroxyquinoline was prepared as described inexample 20. ii) Preparation of3-cyano-7-fluoro-4-hydroxy-5-(tetrahydro-2H-pyran-4-yloxy)quinoline

A mixture of 3-cyano-5,7-difluoro-4-hydroxyquinoline (2.06 g),tetrahydro-2H-pyran-4-ol (1.02 g) and potassium tert-butoxide (1.0Msolution in tetrahydrofuran; 30.0 ml) in anhydrous tetrahydrofuran (100ml) was stirred and heated under nitrogen at 60° C. for 1.5 hours.Acetic acid was added until pH6 was reached and then the solution wasevaporated to dryness. The residue was dissolved in aqueous sodiumhydroxide solution (2.0M) and the resulting solution was filteredthrough a GF/A glass fibre pad. The filtrate was acidified to pH5 withacetic acid and the resulting oily precipitate allowed to stand 3 dayswhen it had become solid. The solid was collected and washed with waterthen air-dried. (1.8 g, 62%); NMR spectrum: (DMSOd₆) 1.67 (m, 2H), 1.92(m, 2H), 3.50 (m, 2H), 3.91 (m, 2H), 4.76 (m, 1H), 6.81 (m, 1H), 6.94(m, 1H), 8.52 (s, 1H); Mass spectrum: M+H⁺ 289.

iii) Preparation of3-cyano-4-hydroxy-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinoline

A mixture of3-cyano-7-fluoro-4-hydroxy-5-(tetrahydro-2H-pyran-4-yloxy)quinoline (864mg), 3-morpholin-4-ylpropan-1-ol (876 mg) and potassium tert-butoxide(1.0M solution in tetrahydrofuran; 9.0 ml) in anhydrous dimethylsulphoxide (30 ml) was heated at 60° C. for 8 hours. The solution wascooled and then diluted with water (120 ml). Acetic acid was added untilpH5 was reached. The solution was pumped onto a cation exchangecartridge (Waters Oasis MCX 6.0 g) and washed on with water. The columnwas flushed successively with water (200 ml), methanol/water (1:1; 200ml) and methanol (200 ml). The product was eluted off the column withmethanol containing triethylamine (1%). The fractions containing theproduct were combined and evaporated. The residue was further purifiedby chromatography on a Redisep silica cartridge (40 g) eluting with agradient of methanol in dichloromethane (5–20%). This gave the titlecompound as an white solid (540 mg, 44%); NMR spectrum: (DMSOd₆; 373° K)1.73 (m, 2H), 1.91 (m, 4H), 2.39 (m, 4H), 2.45 (t, 2H), 3.49 (m, 2H),3.58 (m, 4H), 3.95 (m, 2H), 4.10 (t, 2H), 4.64 (m, 1H), 6.46 (d, 1H),6.60 (d, 1H), 8.24 (s, 1H); Mass spectrum: M+H⁺ 414.

iv) Preparation of4-chloro-3-cyano-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinoline

A mixture of3-cyano-4-hydroxy-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinoline(500 mg) and phosphoryl chloride (2.5 ml) in acetonitrile (1.5 ml) wasrefluxed and stirred for 4 hours. After cooling, the solution wasevaporated to dryness. The flask containing the residue was filled withice chips and excess concentrated aqueous ammonia (25 ml) was added.This mixture was allowed to warm up while stirring overnight. Theproduct was filtered off and air-dried. The title compound was obtainedas a white solid (480 mg, 92%); Mass spectrum: M+H⁺ 432.

EXAMPLE 223-Cyano-7-methoxy-4-[4-(4-methoxybut-1-ynyl)-2,3-methylenedioxyanilino]-5-[(1-methylpiperidin-4-yl)oxy]quinolinedihydrochloride salt

A mixture of4-chloro-3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline (165mg) and 4-(4-methoxybut-1-ynyl)-2,3-methylendioxyaniline (131 mg) in1-propanol (10 ml) was treated with a 1.0M solution of hydrogen chloridein diethyl ether (0.5 ml) then stirred and heated at reflux for 2 hours.On cooling a solid precipitated from the reaction mixture. This solidwas collected and washed with 1-propanol. Analysis by LC/MS suggestedthe product was impure. The solid hydrochloride salt and the liquorswere combined and basified with a solution of sodiumbis(trimethylsilyl)amide (1.0M in THF; 1.0 ml) and the solution allowedto stand overnight. The mixture was evaporated and separated bymulti-injection preparative RP HPLC [Kromasil C18 5 μm silica column,100 mm×10 nm; eluted with a mixture of acetonitrile (55%) and 0.1%aqeous ammonia solution (45%)]. After isolation, the component baseswere converted to their dihydrochloride salts in acetonitrile using twoequivalents of a 1.0M solution of hydrogen chloride in diethyl ether.

The main component,3-cyano-7-methoxy-4-[4-(4-methoxybut-1-ynyl)-2,3-methylenedioxyanilino]-5-[(1-methylpiperidin-4-yl)oxy]quinolinedihydrochloride salt, was thus obtained as a yellow solid (51 mg); NMRSpectrum: (DMSOd₆ and CD₃CO₂D, 393K) 2.19 (m, 2H), 2.37 (m, 2H), 2.72(m, 5H), 3.00 (m, 3H), 3.26 (m, 1H), 3.35 (s, 3H), 3.58 (t, 2H), 3.96(s, 3H), 5.00 (m, 1H), 6.10 (s, 2H), 6.85 (m, 2H), 6.92 (s, 1H), 7.05(s, 1H), 8.48 (s, 1H), 9.51 (br, 1H); Mass Spectrum: M+H⁺ 515.

The second component,4-[(4-but-3-en-1-ynyl-2,3-methylendioxy)anilino]-3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinolinedihydrochloride salt, was thus obtained as a yellow solid (18 mg); NMRSpectrum: (DMSOd₆, 393K) 2.18 (m, 2H), 2.35 (m, 2H), 2.70 (s, 3H), 3.09(m, 4H), 3.95 (s, 3H), 5.00 (m, 1H), 5.62 (d, 1H), 5.73 (d, 1H), 6.11(m, 3H), 6.90 (m, 3H), 7.07 (s, 1H), 8.51 (s, 1H), 9.55 (br, 1H); MassSpectrum: M+H⁺ 483.

The third component,4-[4-(1-chloro-4-methoxybut-1-enyl)-2,3-methylenedioxyanilino]-3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinolinedihydrochloride salt, was thus obtained as a yellow solid (2.1 mg); MassSpectrum: M+H⁺ 551. (The stereochemistry of the double bond was notestablished.)

4-Chloro-3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline usedas a starting material was prepared as described in example 20.

4-(4-methoxybut-1-yn-1-yl)-2,3-methylendioxyaniline used as a startingmaterial was prepared as follows:

A solution of 4-iodo-2,3-methylenedioxyaniline (1.32 g, 5.00 mmol) and4-methoxybut-1-yne (0.84 g, 10.00 mmol) in ethyl acetate (25 ml) wascooled in ice-methanol, under an atmosphere of nitrogen, then treatedwith bis(triphenylphosphine) palladium(II) dichloride (350 mg, 10 mol %)followed by copper(I) iodide (95 mg, 10 mol %) and diisopropylamine(1.40 ml, 10.0 mmol). The reaction was stirred for 2 hours in thecooling bath and then allowed to warm to room temperature over 4 hours:The mixture was filtered through Celite and the filtrate was thenpurified by column chromatography on silica using a gradient of methanolin dichloromethane (0–2%) as eluent to give4-(4-methoxybut-1-yn-1-yl)-2,3-methylendioxyaniline (524 mg, 82%) as adark oil; LCMS: M+H⁺ 220 (82%).

4-Methoxybut-1-yne is described in Aust. J. Chem. 1988, 41(2), 251 261.

4-iodo-2,3-methylenedioxyaniline was prepared as described in example 1.

EXAMPLE 233-cyano-4-[6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinolinedihydrochloride salt

A mixture of4-chloro-3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline (203mg) and 6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylendioxyaniline (139mg) in dry dimethylformamide (6 ml) was stirred at room temperature.Sodium bis(trimethylsilyl)amide (1.0M solution in tetrahydrofuran; 1.35ml) was added and then the mixture was allowed to warm to roomtemperature over one hour. The reaction mixture was acidified withacetic acid (2.0 ml) and the solvent was evaporated under high vacuum.The residue was dissolved in a mixture of dichloromethane and methanol(9:1) and the mixture preabsorbed onto silica gel (kieselgel 60; 2.5 g).The solvent was evaporated and the solid packed into a preloadcartridge. This was then purified by chromatography on a 40 g silicaRedisep cartridge using gradient elution [0.5% to 3% ammonia solution(7.0M in methanol) in dichloromethane]. Fractions containing therequired product were combined and evaporated to give the free base (240mg). This material was dissolved in ethanol (10 ml) and treated with 2equivalents of 1.0M hydrogen chloride in diethyl ether. The solventswere evaporated and the residue was dissolved in acetonitrile (10 ml).The title compound crystallised on standing overnight as a pale yellowsolid (158 mg); NMR Spectrum: (DMSOd₆, 373K) 2.21 (m, 2H), 2.41 (m, 2H),2.76 (s, 3H), 3.15 (m, 2H), 3.47 (s, 3H), 3.49 (m, 2H), 3.97 (s, 3H),4.36 (s, 2H), 5.04 (m, 1H), 6.16 (s, 2H), 6.97 (m, 1H), 7.07 (s, 1H),7.13 (s, 1H), 8.56 (s; 1H), 9.73 (br, 1H), 10.75 (br, 1H); MassSpectrum: M+H⁺ 535.

4-Chloro-3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline usedas a starting material was prepared as described in example 20.

6-Chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylendioxyaniline used as astarting material was prepared as follows:

Sulphuryl chloride (72.5 ml) was added dropwise during 1.7 hours to astirred mixture of benzodioxole (100 g), aluminium trichloride (0.43 g)and diphenyl sulphide (0.55 ml). Once the reaction started with theevolution of sulphur dioxide, the reaction mixture was cooled in a waterbath to a temperature of approximately 22° C. After completion of theaddition, the reaction mixture was stirred at ambient temperature for 45minutes. The reaction mixture was degassed under vacuum and filtered andthe filtrate was distilled at atmospheric pressure using a Vigreuxdistillation column. There was thus obtained 5-chloro-1,3-benzodioxole;b.p. 185–187° C.; NMR Spectrum: (CDCl₃) 6.0 (s, 2H); 6.7 (d, 1H);6.75–6.9 (m, 2H).

A mixture of diisopropylamine (4.92 ml) and THF (100 ml) was cooled to−78° C. and n-butyllithium (2.5 M in hexane, 14 ml) was added dropwise.The mixture was stirred at −78° C. for 15 minutes.5-Chloro-1,3-benzodioxole (3.73 ml) was added dropwise and the reactionmixture was stirred at −78° C. for 30 minutes. Dry carbon dioxide gaswas bubbled into the reaction mixture for 30 minutes. The resultantreaction mixture was allowed to warm to ambient temperature and wasstirred for a further hour. Water was added and the organic solvent wasevaporated. The residue was acidified to pH2 by the addition of 2Naqueous hydrochloric acid solution. The resultant solid was isolated andwashed in turn with water and diethyl ether. There was thus obtained5-chloro-1,3-benzodioxole-4-carboxylic acid (5.4 g); NMR Spectrum:(DMSOd₆) 6.15 (s, 2H), 7.0 (m, 2H), 13.7 (br s, 1H).

A portion (1 g) of the material so obtained was dissolved in 1,4-dioxane(15 ml) and anhydrous tert-butanol (4 ml), diphenylphosphoryl azide(1.12 ml) and triethylamine (0.73 ml) were added in turn. The resultantmixture was stirred and heated to 100° C. for 4 hours. The mixture wasevaporated and the residue was partitioned between ethyl acetate and a5% aqueous citric acid solution. The organic phase was washed in turnwith water, a saturated aqueous sodium bicarbonate solution and brine,dried over magnesium sulphate and evaporated. The residue was purifiedby column chromatography on silica using a 9:1 mixture of petroleumether (b.p. 40–60° C.) and ethyl acetate as eluent. There was thusobtained tert-butyl 5-chloro-1,3-benzodioxol-4-ylcarbamate (1.1 g); NMRSpectrum: (DMSOd₆) 1.45 (s, 9H), 6.1 (s, 2M), 6.85 (d, 1H), 6.95 (d,1H), 8.75 (s, 1H).

A mixture of the material so obtained (1.1 g), trifluoroacetic acid (6ml) and methylene chloride (20 ml) was stirred at ambient temperaturefor 3 hours. The solvent was evaporated and the residue was partitionedbetween ethyl acetate and a saturated aqueous sodium bicarbonatesolution. The organic phase was washed with brine, dried over magnesiumsulphate and evaporated. There was thus obtained6-chloro-2,3-methylenedioxyaniline (0.642 g); NMR Spectrum: (DMSOd₆)5.15 (s, 2H), 6.0 (s, 2H), 6.25 (d, 1H), 6.75 (d, 1H).

Benzyltrimethylammonium dichloroiodate (6.7 g) was added portionwiseover 10 minutes to a stirred mixture of6-chloro-2,3-methylenedioxyaniline (3 g), calcium carbonate (2.28 g) inmethanol (15 ml) and dichloromethane (30 ml). The reaction mixture wasstirred at ambient temperature for 1.5 hours. The reaction mixture wasdiluted with water and extracted with dichloromethane. The organics werewashed with water, saturated brine and dried over magnesium sulfate. Theresidue was purified by column chromatography on silica using a gradientof an 8:1 mixture of dichloromethane/isohexane to dichloromethane aseluent. There was thus obtained 6-chloro-4-iodo-2,3-methylendioxyanilineas a black crystalline solid (4.82 g); NMR Spectrum: (DMSOd₆) 6.04 (s,2H), 7.00 (s, 1H).

Bis(Triphenyl-phosphine)palladium(II) chloride (472 mg), copper iodide(192 mg) and diisopropylamine (680 mg) were added to a stirred solutionof 6-chloro-4-iodo-2,3-methylenedioxyaniline (1000 mg) and methylpropargyl ether (471 mg) in ethyl acetate (10 mls) at −20° C. Thereaction was allowed to warm to ambient temperature over 16 hours. Thereaction mixture was partitioned between ethyl acetate and saturatedNaHCO3. The organics were washed with water and saturated brine anddried over magnesium sulfate. The product was purified by columnchromatography on silica using a gradient of 80–100%Dichloromethane/isohexane as eluent.6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylendioxyaniline was thusobtained as a tan crystalline solid (200 mg); NMR Spectrum: (DMSOd₆)3.28 (s, 3H), 4.26 (s, 2H), 5.52 (s, 2H), 6.05 (s, 2H), 6.93 (s, 1H).

EXAMPLE 243-cyano-6,7-dimethoxy-4-[2,3-methylenedioxy-4-(pyridin-2-ylethynyl)anilino]quinolinedihydrochloride salt

Using an analogous procedure to that described in Example 1,3-cyano-4-(4-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinoline wasreacted with 2-ethynylpyridine. The reaction mixture was partitionedbetween methylene chloride and a 2N aqueous hydrochloric acid solution.This resulted in the precipitation of the product which was filtered,washed with dichloromethane, ethanol and diethyl ether and dried to givethe title compound as as a yellow solid (53%); NMR Spectrum: (DMSOd₆)4.00 (s, 3H), 4.02 (s, 3H), 6.19 (s, 2H), 7.07 (d, 1H), 7.19 (d, 1H),7.43–7.49 (m, 1H), 7.50 (s, 1H), 7.68 (d, 1H), 7.88 (t, 1H), 8.21 (s,1H), 8.63 (d, 1H), 9.08 (s, 1H); Mass Spectrum: M+H⁺ 451.05.

1. A quinoline derivative of the Formula I

wherein Z¹ is an O, S, SO, SO₂, N(R²) or C(R²)₂ group, wherein each R²group, which may be the same or different, is hydrogen or (1–6C)alkyl; mis 0, 1, 2, 3 or 4; each R¹ group, which may be the same or different,is selected from halogeno, trifluoromethyl, cyano, isocyano, nitro,hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, (1–6C)alkyl,(2–8C)alkenyl, (2–8C)alkynyl, (1–6C)alkoxy, (2–6C)alkenyloxy,(2–6C)alkynyloxy, (1–6C)alkylthio, (1–6C)alkylsulphinyl,(1–6C)alkylsulphonyl, (1–6C)alkylamino, di-[(1–6C)alkyl]amino,(1–6C)alkoxycarbonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl, (2–6C)alkanoyloxy,(2–6C)alkanoylamino, N-(1–6C)alkyl-(2–6C)alkanoylamino,(3–6C)alkenoylamino, N-(1–6C)alkyl-(3–6C)alkenoylamino,(3–6C)alkynoylamino, N-(1–6C)alkyl-(3–6C)alkynoylamino,N-(1–6C)alkylsulphamoyl N,N-di-[(1–6C)alkyl]sulphamoyl,(1–6C)alkanesulphonylamino, N-(1–6C)alkyl-(1–6C)alkanesulphonylamino orfrom a group of the formula: wherein X¹ is a direct bond or is selectedfrom O, S, SO, SO₂, N(R⁴), CO, CH(OR⁴), CON(R⁴), N(R⁴)CO, SO₂N(R⁴),N(R⁴)SO₂, OC(R⁴)₂, SC(R⁴)₂ and N(R⁴)C(R⁴)₂, wherein R⁴ is hydrogen or(1–6C)alkyl, and Q¹ is aryl, aryl-(1–6C)alkyl, (3–7C)cycloalkyl,(3–7C)cycloalkyl-(1–6C)alkyl, (3–7C)cycloalkenyl,(3–7C)cycloalkenyl-(1–6C)alkyl, heteroaryl, heteroaryl-(1–6C)alkyl,heterocyclyl or heterocyclyl-(1–6C)alkyl, or (R¹)_(m) is(1–3C)alkylenedioxy, and wherein adjacent carbon atoms in any(2–6C)alkylene chain within a R¹ substituent are optionally separated bythe insertion into the chain of a group selected from O, S, SO, SO₂,N(R⁵), CO, CH(OR⁵), CON(R⁵), N(R⁵)CO, SO₂N(R⁵), N(R⁵)SO₂, CH═CH and C≡Cwherein R⁵ is hydrogen or (1–6C)alkyl or, when the inserted group isN(R⁵), R⁵ may also be (2–6C)alkanoyl, and wherein any CH₂═CH— or HC≡C—group within a R¹ substituent optionally bears at the terminal CH₂═ orHC≡ position a substituent selected from halogeno, carboxy, carbamoyl,(1–6C)alkoxycarbonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, amino-(1–6C)alkyl,(1–6C)alkylamino-(1–6C)alkyl, di-[(1–6C)alkyl]amino-(1–6C)alkyl or froma group of the formula:Q²-X²— wherein X² is a direct bond or is selected from CO and N(R⁶)CO,wherein R⁶ is hydrogen or (1–6C)alkyl, and Q² is aryl, aryl-(1–6C)alkyl,heteroaryl, heteroaryl-(1–6C)alkyl, heterocyclyl orheterocyclyl-(1–6C)alkyl, and wherein any CH, CH₂ or CH₃ group within aR¹ substituent optionally bears on each said CH, CH₂ or CH₃ group one ormore halogeno or (1–6C)alkyl substituents or a substituent selected fromhydroxy, cyano, amino, carboxy, carbamoyl, (1–6C)alkoxy,(1–6C)alkylthio, (1–6C)alkylsulphinyl, (1–6C)alkylsulphonyl,(1–6C)alkylamino, di-[(1–6C)alkyl]amino, (1–6C)alkoxycarbonyl,N-(1–6C)alkylcarbamoyl, N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl,(2–6C)alkanoyloxy, (2–6C)alkanoylamino,N-(1–6C)alkyl-(2–6C)alkanoylamino, N-(1–6C)alkylsulphamoyl, NN-di-[(1–6C)alkyl]sulphamoyl, (1–6C)alkanesulphonylamino,N-(1–6C)alkyl-(1–6C)alkanesulphonylamino or from a group of the formula:—X³-Q³ wherein X3 is a direct bond or is selected from I, S, SO, SO₂,N(R⁷), CO, CH(OR⁷), CON(R⁷), N(R⁷)CO, SO₂N(R⁷), N(R⁷)SO₂, C(R⁷)₂O,C(R⁷)₂S and N(R⁷)C(R⁷)₂, wherein R⁷ is hydrogen or (1–6C)alkyl, and Q³is aryl, aryl-(1–6C)alkyl, (3–7C)cycloalkyl,(3–7C)cycloalkyl-(1–6C)alkyl, (3–7C)cycloalkenyl,(3–7C)cycloalkenyl-(1–6C)alkyl, heteroaryl, heteroaryl-(1–6C)alkyl,heterocyclyl or heterocyclyl-(1–6C)alkyl, and wherein any aryl,heteroaryl or heterocyclyl group within a substituent on R¹ optionallybears 1, 2 or 3 substituents, which may be the same or different,selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino,carboxy, carbamoyl, (1–6C)alkyl, (2–8C)alkenyl, (2–8C)alkynyl,(1–6C)alkoxy, (2–6C)alkenyloxy, (2–6C)alkynyloxy, (1–6C)alkylthio,(1–6C)alkylsulphinyl, (1–6C)alkylsulphonyl, (1–6C)alkylamino,di-[(1–6C)alkyl]amino, (1–6C)alkoxycarbonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl, (2–6C)alkanoyloxy,(2–6C)alkanoylamino, N-(1–6C)alkyl-(2–6C)alkanoylamino,N-(1–6C)alkylsulphamoyl, N N-di-[(1–6C)alkyl]sulphamoyl,(1–6C)alkanesulphonylamino, N-(1–6C)alkyl-(1–6C)alkanesulphonylamino orfrom a group of the formula:—X⁴—R⁸ wherein X⁴ is a direct bond or is selected from O and N(R⁹),wherein R is hydrogen or (1–6C)alkyl, and R⁸ is halogeno-(1–6C)alkyl,hydroxy-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl,amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl,di-[(1–6C)alkyl]amino-(1–6C)alkyl, (2–6C)alkanoylamino-(1–6C)alkyl or(1–6C)alkoxycarbonylamino-(1–6C)alkyl or from a group of the formula:—X⁵-Q⁴ wherein X⁵ is a direct bond or is selected from O, N(R¹⁰) and CO,wherein R¹⁰ is hydrogen or (1–6C)alkyl, and Q⁴ is aryl,aryl-(1–6C)alkyl, heteroaryl, heteroaryl-(1–6C)alkyl, heterocyclyl orheterocyclyl-(1–6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1–6C)alkyl,(2–8C)alkenyl, (2–8C)alkynyl and (1–6C)alkoxy, and wherein anyheterocyclyl group within a substituent on R¹ optionally bears 1 or 2oxo or thioxo substituents; n is 0, 1,2 or 3; each R³ group is halogeno,trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl,(1–6C)alkyl, (2–8C)alkenyl, (2–8C)alkynyl, (1–6C)alkoxy,(2–6C)alkenyloxy, (2–6C)alkynyloxy, (1–6C)alkylthio,(1–6C)alkylsulphinyl, (1–6C)alkylsulphonyl, (1–6C)alkylamino,di-[(1–6C)alkyl]amino, (1–6C)alkoxycarbonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl, (2–6C)alkanoyloxy,(2–6C)alkanoylamino, N-(1–6C)alkyl-(2–6C)alkanoylamino,(3–6C)alkenoylamino, N-(1–6C)alkyl-(3–6C)alkenoylamino,(3–6C)alkynoylamino, N-(1–6C)alkyl-(3–6C)alkynoylamino,N-(1–6C)alkylsulphamoyl N,N-di-[(1–6C)alkyl]sulphamoyl,(1–6C)alkanesulphonylamino N-(1–6C)alkyl-(1–6C)alkanesulphonylamino orfrom a group of the formula:—X⁶—R¹¹ wherein X⁶ is a direct bond or is selected from O and N(R¹²),wherein R¹² is hydrogen or (1–6C)alkyl, and R¹¹ is halogeno-(1–6C)alkyl,hydroxy-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl,amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl ordi-[(1–6C)alkyl]amino-(1–6C)alkyl; Z² is a C≡C or C(R¹³)═C(R¹³) group,wherein each R¹³ group, which may be the same or different, is hydrogenor (1–6C)alkyl; and R¹⁴ is selected from halogeno, cyano, isocyano,formyl, carboxy, carbamoyl, (2–8C)alkenyl, (2–8C)alkynyl,(1–6C)alkoxycarbonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl, N-(1–6C)alkylsulphamoyl,N,N-di-[(1–6C)alkyl]sulphamoyl, halogeno-(1–6C)alkyl,hydroxy-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl,amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl,di-[(1–6C)alkyl]amino-(1–6C)alkyl, (2–6C)alkanoylamino-(1–6C)alkyl,(1–6C)alkoxycarbonylamino-(1–6C)alkyl or from a group of the formula:—X⁷-Q⁵ wherein X⁷ a direct bond or is selected from CO, CH(OR¹⁵),CON(R¹⁵) or SO₂N(R¹⁵), wherein R¹⁵ is hydrogen or (1–6C)alkyl, and Q⁵ isaryl, aryl-(1–6C)alkyl, (3–7C)cycloalkyl, (3–7C)cycloalkyl-(1–6C)alkyl,heteroaryl, heteroaryl-(1–6C)alkyl, heterocyclyl orheterocyclyl-(1–6C)alkyl, and wherein any CH, CH₂ or CH₃ group within aR¹⁴ substituent optionally bears on each said CH, CH₂ or CH₃ group oneor more halogeno or (1–6C)alkyl substituents or a substituent selectedfrom hydroxy, cyano, amino, carboxy, carbamoyl, (1–6C)alkoxy,(1–6C)alkylthio, (1–6C)alkylsulphinyl, (1–6C)alkylsulphonyl,(1–6C)alkylamino, di-[(1–6C)alkyl]amino, (1–6C)alkoxycarbonyl,N-(1–6C)alkylcarbamoyl, N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl,(2–6C)alkanoyloxy, (2–6C)alkanoylaminoN-(1–6C)alkyl-(2–6C)alkanoylamino, N-(1–6C)alkylsulphamoyl,N,N-di-[(1–6C)alkyl]-sulphamoyl, (1–6C)alkanesulphonylamino,N-(1–6C)alkyl-(1–6C)alkanesulphonylamino or from a group of the formula:—X⁸-Q⁶ wherein X⁸ is a direct bond or is selected from O, S, SO, SO₂,N(R¹⁶), CO, CH(OR¹⁶), CON(R¹⁶), N(R¹⁶)CO, SO₂N(R¹⁶), N(R¹⁶)SO₂,C(R¹⁶)₂O, C(R¹⁶)₂S and N(R¹⁶)C(R¹⁶)₂, wherein R¹⁶ is hydrogen or(1–6C)alkyl, and Q⁶ is aryl, aryl-(1–6C)alkyl, (3–7C)cycloalkyl,(3–7C)cycloalkyl-(1–6C)alkyl, (3–7C)cycloalkenyl,(3–7C)cycloalkenyl-(1–6C)alkyl, heteroaryl, heteroaryl-(1–6C)alkyl,heterocyclyl or heterocyclyl-(1–6C)alkyl, and wherein any aryl,heteroaryl or heterocyclyl group within a substituent on R¹⁴ optionallybears 1, 2 or 3 substituents, which may be the same or different,selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino,carboxy, carbamoyl, (1–6C)alkyl, (2–8C)alkenyl, (2–8C)alkynyl,(1–6C)alkoxy, (2–6C)alkenyloxy, (2–6C)alkynyloxy, (1–6C)alkylthio,(1–6C)alkylsulphinyl, (1–6C)alkylsulphonyl, (1–6C)alkylamino,di-[(1–6C)alkyl]amino, (1–6C)alkoxycarbonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl, (2–6C)alkanoyloxy,(2–6C)alkanoylamino N-(1–6C)alkyl-(2–6C)alkanoylamino,N-(1–6C)alkylsulphamoyl, N,N-di-[(1–6C)alkyl]-sulphamoyl,(1–6C)alkanesulphonylamino, N-(1–6C)alkyl-(1–6C)alkanesulphonylamino orfrom a group of the formula:—X⁹—R¹⁷ wherein X⁹ is a direct bond or is selected from O and N(R¹⁸),wherein R¹⁸ is hydrogen or (1–6C)alkyl, and R¹⁷ is halogeno-(1–6C)alkyl,hydroxy-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl,amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl,di-[(1–6C)alkyl]amino-(1–6C)alkyl, (2–6C)alkanoylamino-(1–6C)alkyl,(1–6C)alkoxycarbonylamino-(1–6C)alkyl, or from a group of the formula:—X¹⁰-Q⁷ wherein X¹⁰ is a direct bond or is selected from O, N(R¹⁹) andCO, wherein R¹⁹ is hydrogen or (1–6C)alkyl, and Q⁷ is aryl,aryl-(1–6C)alkyl, heteroaryl, heteroaryl-(1–6C)alkyl, heterocyclyl orheterocyclyl-(1–6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1–6C)alkyl,(2–8C)alkenyl, (2–8C)alkynyl and (1–6C)alkoxy, and wherein anyheterocyclyl group within a substituent on R¹⁴ optionally bears 1 or 2oxo or thioxo substituents; or a pharmaceutically-acceptable saltthereof.
 2. A quinoline derivative of the Formula I, or apharmaceutically acceptable salt thereof, according to claim 1 whereinR¹, R³, Z¹, Z², m and n have any of the meanings defined in claim 1 andR¹⁴ is selected from cyano, formyl, carboxy, carbamoyl, methoxycarbonyl,vinyl, ethoxycarbonyl, N-methylcarbamoyl, N-ethylcarbamoyl,N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl,acetyl, propionyl, chloromethyl, 2-chloroethyl, 3-chioropropyl,hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl,2-methoxyethyl, 3-methoxypropyl or from a group of the formula:—X⁷-Q⁵ wherein X⁷ is a direct bond or CO and Q⁵ is pyridin-2-yl,1-pyrrolidinyl, morpholino, 1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl,piperidino, 1-homopiperidinyl, piperazin-1-yl, homopiperazin-1-yl,1-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl,1-homopiperidinylmethyl, 1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl,piperazin-1-ylmethyl, homopiperazin-1-ylmethyl or 3-morpholinopropyl,and wherein any CH₂ or CH₃ group within a R¹⁴ substituent optionallybears on each said CH₂ or CH₃ group one or more fluoro, chloro or methylgroups or a substituent selected from hydroxy, amino, methoxy,methylamino, dimethylamino, acetoxy, acetamido and N-methylacetamido,and wherein any heteroaryl or heterocyclyl group within a sub stituenton R¹⁴ optionally bears 1, 2 or 3 substituents, which may be the same ordifferent, selected from hydroxy, amino, carbamoyl, methyl, ethyl,allyl, 2-propynyl, methoxy, methylsulphonyl, N-methylcarbamoyl,N,N-dimethylcarbamoyl and acetyl, or optionally bears 1 substituentselected from a group of the formula:—X⁹—R¹⁷ wherein X⁹ is a direct bond and R¹⁷ is 2-fluoroethyl,2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl,cyanomethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl,acetamidomethyl, methoxycarbonylaminomethyl, ethoxycarbonylaminomethylor tert-butoxycarbonylaminomethyl, and wherein any heterocyclyl groupwithin a substituent on R¹⁴ optionally bears 1 or 2 oxo substituents. 3.A quinoline derivative of the Formula I according to claim 1 wherein: Z¹is O or NH; m is 1 and the R¹ group is located at the 5-, 6- or7-position or m is 2 and each R¹ group, which may be the same ordifferent, is located at the 5- and 7-positions or at the 6- and7-positions and R¹ is selected from hydroxy, amino, methyl, ethyl,propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy,pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino,diethylamino, acetamido, propionamido, 2-imidazol-1-ylethoxy,2-(1,2,4-triazol-1-yl)ethoxy, tetrahydrofuran-3-yloxy,tetrahydropyran-4-yloxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy,pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,4-morpholinobutoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy,piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy,2-piperidin-3-ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy,3-piperidin-4-ylpropoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy,2-homopiperazin-1-ylethoxy and 3-homopiperazin-1-ylpropoxy, and whereinadjacent carbon atoms in any (2–6C)alkylene chain within a R¹substituent are optionally separated by the insertion into the chain ofa group selected from O, NH, N(Me), CH═CH and C≡C, and wherein any CH₂or CH₃ group within a R¹ substituent optionally bears on each said CH₂or CH₃ group one or more fluoro or chloro groups or a substituentselected from hydroxy, amino, methoxy, methylsulphonyl, methylamino,dimethylamino, diethylamino, N-ethyl-N-methylamino,N-isopropyl-N-methylamino, N-methyl-N-propylamino and acetoxy, andwherein any heteroaryl or heterocyclyl group within a substituent on R¹optionally bears 1 or 2 substituents, which may be the same ordifferent, selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, carbamoyl, methyl, ethyl, methoxy, N-methylcarbamoyl andN,N-dimethylcarbamoyl and a pyrrolidin-2-yl, piperidin-3-yl,piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within a R¹substituent is optionally N-substituted with allyl, methylsulphonyl,acetyl, 2-fluoroethyl, 3-fluoropropyl, 2-methoxyethyl, 3-methoxypropyl,cyanomethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl,3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl,2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 2-morpholinoethyl,3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, the last 8 of whichsubstituents each optionally bears 1 or 2 substituents, which may be thesame or different, selected from fluoro, chloro, methyl and methoxy, andwherein any heterocyclyl group within a substituent on R¹ optionallybears 1 or 2 oxo substituents; n is 0 or 1 and the R³ group, if present,is located at the 5- or 6-position of the 1,3-benzodioxol-4-yl group andis selected from fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy,methyl, ethyl, vinyl, allyl, ethynyl, methoxy and ethoxy; Z² is a C≡C orCH═CH group; and R¹⁴ is selected from cyano, formyl, carboxy, carbamoyl,methoxycarbonyl, vinyl, ethoxycarbonyl N-methylcarbamoyl,N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl,N,N-diethylcarbamoyl, acetyl, propionyl, chloromethyl, 2-chloroethyl,3-chloropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl,2-cyanoethyl, 3-cyanopropyl, methylaminomethyl, ethylaminomethyl,2-methylaminoethyl, 3-methylaminopropyl, 2-ethylaminoethyl,3-ethylaminopropyl, dimethylaminomethyl, 2-dimethylaminoethyl,3-dimethylaminopropyl, acetamidomethyl, 2-acetamidoethyl and3-acetamidopropyl, or from a group of the formula:—X⁷-Q⁵ wherein X⁷ is a direct bond or CO and Q⁵ is pyridin-2-yl,1-pyrrolidinyl, morpholino, 1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl,piperidino, 1-homopipendinyl, piperazin-1-yl, homopiperazin-1-yl,1-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl,1-homopiperidinylmethyl, 1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl,piperazin-1-ylmethyl, homopiperazin-1-ylmethyl or 3-morpholinopropyl,and wherein any CH₂ or CH₃ group within a R¹⁴ substituent optionallybears on each said CH₂ or CH₃ group one or more fluoro, chloro or methylgroups or a substituent selected from hydroxy, amino, methoxy,methylamino, dimethylamino, acetoxy, acetamido and N-methylacetamido,and wherein any heteroaryl or heterocyclyl group within a sub stituenton R¹⁴ optionally bears 1, 2 or 3 substituents, which may be the same ordifferent, selected from hydroxy, amino, carbamoyl, methyl, ethyl,allyl, 2-propynyl, methoxy, methylsulphonyl, N-methylcarbamoyl,N,N-dimethylcarbamoyl and acetyl, or optionally bears 1 substituentselected from a group of the formula:—X⁹—R¹⁷ wherein X⁹ is a direct bond and R¹⁷ is 2-hydroxyethyl,3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl,aminomethyl, methylaminomethyl, dimethylaminomethyl, acetamidomethyl,methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl ortert-butoxycarbonylaminomethyl, and wherein any heterocyclyl groupwithin a substituent on R¹⁴ optionally bears 1 or 2 oxo substituents; ora pharmaceutically-acceptable acid-addition salt thereof.
 4. A quinolinederivative of the Formula I, or a pharmaceutically acceptable saltthereof, according to claim 1 wherein R¹, R³, R¹⁴, Z², m and n have anyof the meanings defined in claim 1 and Z¹ is NH.
 5. A quinolinederivative of the Formula I, or a pharmaceutically acceptable saltthereof, according to claim 1 wherein R¹, R³, R¹⁴, Z¹, m and n have anyof the meanings defined in claim 1 and Z² is a C≡C group.
 6. A quinolinederivative of the Formula I, or a pharmaceutically acceptable saltthereof, according to claim 1 wherein R¹, R³, R¹⁴, Z¹, Z², m and n haveany of the meanings defined in claim 1 and the Z²-R¹⁴ group is locatedat the 7-position on the 1,3-benzodioxol-4-yl group.
 7. A quinolinederivative of the Formula I according to claim 1 wherein: Z¹ is NH; m is2 and the first R¹ group is a 6-methoxy group and the second R¹ group islocated at the 7-position and is selected from methoxy, ethoxy,2-fluoroethoxy, 2-chloroethoxy, 3-fluoropropoxy, 3-chloropropoxy,2-(2-chloroethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 3-(4-allylpiperazin-1-yl)propoxy,3-(4-methylsulphonylpiperazin-1-yl)propoxy,3-(4-acetylpiperazin-1-yl)propoxy,2-(4-cyanomethylpiperazin-1-yl)ethoxy,3-(4-cyanomethylpiperazin-1-yl)propoxy,2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy,3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy,2-(3-oxopiperazin-1-yl)ethoxy, 3-(3-oxopiperazin-1-yl)propoxy,2-(2-pyrrolidin-1-ylethoxy)ethoxy and2-fluoro-3-(4-hydroxypiperidin-1-yl)propoxy; n is 0 or n is 1 and R³ isa fluoro or chloro group located at the 5-position of the1,3-benzodioxol-4-yl group; the -Z²-R¹⁴ group is located at the7-position on the 1,3-benzodioxol-4-yl group, Z² is a C≡C group; and R¹⁴is selected from vinyl, hydroxymethyl, methoxymethyl,dimethylaminomethyl, pyridin-2-yl, 1-pyrrolidinylmethyl,morpholinomethyl, piperidinomethyl,1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylmethyl and piperazin-1-ylmethyl;or a pharmaceutically-acceptable acid-addition salt thereof.
 8. Aquinoline derivative of the Formula I according to claim 1 wherein Z¹ isNH; m is 2 and the first R¹ group is located at the 5-position and isselected from N-methylpiperidin-4-yloxy and tetrahydro-2H-pyran-4-yloxyand the second R¹ group is located at the 7-position and is selectedfrom methoxy and 3-morpholinopropoxy, n is 0 or n is 1 and R³ is locatedat the 5-position of the 1,3-benzodioxol-4-yl group and is a chlorogroup; the -Z²-R¹⁴ group is located at the 7-position on the 1,3-benzodioxol-4-yl group, Z² is a C≡C group; and R¹⁴ is selected frommethoxymethyl and 2-methoxyethyl; or a pharmaceutically-acceptableacid-addition salt thereof.
 9. A quinoline derivative of the Formula Iaccording to claim 1 and selected from7-[3-(4-acetylpiperazin-1-yl)propoxy]-3-cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline;3-cyano-6,7-dimethoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline;3-cyano-6,7-dimethoxy-4-[6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline;3-cyano-7-ethoxy-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline;3-cyano-7-{3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy}-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline;3-cyano-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline;3-cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]-7-[3-morpholinopropoxy]quinoline;4-[6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]-3-cyano-6-methoxy-7-[3-morpholinopropoxy]quinoline;3-cyano-7-[3-(1,1-dioxotetrahydro-4H-thiazin-4-yl)propoxy]-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline;3-cyano-7-(2-fluoroethoxy)-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline;3-cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]-7-[3-(3-oxopiperazin-1-yl)propoxy]quinoline;3-cyano-6-methoxy-4-[6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]-7-[3-(3-oxopiperazin-1-yl)propoxy]quinoline;3-cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]-7-[2-(2-pyrrolidin-1-ylethoxy)ethoxy]quinoline;3-cyano-6-methoxy-7-[2-(2-methoxyethoxy)ethoxy]-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline;3-cyano-4-[6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline;3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline;3-cyano-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline;3-cyano-7-methoxy-4-[4-(4-methoxybut-1-ynyl)-2,3-methylenedioxyanilino]-5-[(1-methylpiperidin-4-yl)oxy]quinoline;4-[(4-but-3-en-1-ynyl-2,3-methylendioxy)anilino]-3-cyano-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline;3-cyano-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]-4-[6-fluoro-4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline;3-cyano-6-methoxy-7-[2-fluoro-3-(4-hydroxypiperidin-1-yl)propoxy]-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline;3-cyano-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline;and3-cyano-6,7-dimethoxy-4-[4-(pyridin-2-ylethynyl)-2,3-methylenedioxyanilino]quinoline,or a pharmaceutically acceptable acid addition salt thereof.
 10. Aprocess for the preparation of a quinoline derivative of the Formula I,or a pharmaceutically-acceptable salt thereof, according to claim 1which comprises: (a) for the production of those compounds of theFormula I wherein Z¹ is an O, S or N(R²) group, the reaction of aquinoline of the Formula II

wherein L is a displaceable group and m and R¹ have any of the meaningsdefined in claim 1 except that any functional group is protected ifnecessary, with a compound of the Formula III

wherein Z¹ is O, S, or N(R²) and n, R³, R², Z² and R¹⁴ have any of themeanings defined in claim 1 except that any functional group isprotected if necessary, whereafter any protecting group that is presentis removed by conventional means; (b) for the production of thosecompounds of the Formula I wherein at least one R¹ group is a group ofthe formulaQ¹-X¹— wherein Q¹ is an aryl-(1–6C)alkyl, (3–7C)cycloalkyl-(1–6C)alkyl,(3–7C)cycloalkenyl-(1–6C)alkyl, heteroaryl-(1–6C)alkyl orheterocyclyl-(1–6C)alkyl group or an optionally substituted alkyl groupand X¹ is an oxygen atom, the coupling, conveniently in the presence ofa suitable dehydrating agent, of a quinoline of the Formula V

wherein m, R¹, Z¹, n, R³, Z² and R¹⁴ have any of the meanings defined inclaim 1 except that any functional group is protected if necessary, withan appropriate alcohol of the formula Q¹-OH wherein any functional groupis protected if necessary, whereafter any protecting group that ispresent is removed by conventional means; (c) for the production ofthose compounds of the Formula I wherein R¹ is an amino-substituted(1–6C)alkoxy group, the reaction of a compound of the Formula I whereinR¹ is a halogeno-substituted (1–6C)alkoxy group with a heterocyclylcompound or an appropriate amine; (d) for the production of thosecompounds of the Formula I wherein an R¹ group contains a (1–6C)alkoxyor substituted (1–6C)alkoxy group or a (1–6C)alkylamino or substituted(1–6C)alkylamino group, the alkylation, conveniently in the presence ofa suitable base of a quinoline derivative of the Formula I, wherein theR¹ group contains a hydroxy group or a primary or secondary amino group;(e) for the production of those compounds of the Formula I wherein Z¹ isa SO or SO₂ group, wherein an R¹ or R³ substituent is a(1–6C)alkylsulphinyl or (1–6C)alkylsulphonyl group or wherein an R¹, R³or R¹⁴ substituent contains a SO or SO₂ group, the oxidation of acompound of Formula I wherein Z¹ is a S group or wherein an R¹ or R³substituent is a (1–6C)alkylthio group or wherein an R¹ R³ or R¹⁴substituent contains a S group; (f) the reaction of a compound of theFormula VI

wherein L is a displaceable group and m, R¹, Z¹, n and R³ have any ofthe meanings defined in claim 1 except that any functional group isprotected if necessary, with a compound of the Formula VIIHZ²-R¹⁴  VII wherein Z² is a C≡C or C(R¹³)═C(R¹³) group and R¹³ and R¹⁴have any of the meanings defined in claim 1 except that any functionalgroup is protected if necessary, whereafter any protecting group that ispresent is removed by conventional means; (g) for the production of acompound of the Formula I wherein R¹⁴ is a carboxy group, the cleavageof a compound of the Formula I wherein R¹⁴ is a (1–6C)alkoxycarbonylgroup; (h) the reaction of a compound of the Formula I wherein R¹⁴ is acarboxy group with an appropriate amine to form a further compound ofthe Formula I wherein R¹⁴ is a carbamoyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl or heterocyclylcarbonylamino group; andwhen a pharmaceutically-acceptable salt of a quinoline derivative of theFormula I is required it may be obtained using a conventional procedure.11. A pharmaceutical composition which comprises a quinoline derivativeof the Formula I, or a pharmaceutically-acceptable salt thereof,according to claim 1 in association with a pharmaceutically-acceptablediluent or carrier.